CN102596910A - Androgen receptor modulating compounds - Google Patents

Androgen receptor modulating compounds Download PDF

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CN102596910A
CN102596910A CN2010800483401A CN201080048340A CN102596910A CN 102596910 A CN102596910 A CN 102596910A CN 2010800483401 A CN2010800483401 A CN 2010800483401A CN 201080048340 A CN201080048340 A CN 201080048340A CN 102596910 A CN102596910 A CN 102596910A
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alkyl
pyrazoles
hydrogen
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CN102596910B (en
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G·沃尔法特
O·特尔梅坎加斯
H·萨洛
L·赫格隆德
A·卡尔亚莱宁
P·克努蒂拉
P·霍尔姆
S·拉斯库
A·韦萨莱宁
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Orion Oyj
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Abstract

Compounds of formula (I), wherein R1 to R16, A. B and E are as defined in the claims, and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.

Description

Androgen receptor is regulated compound
Technical field
The present invention relates to be used to treat nuclear receptor, particularly steroid receptor, especially androgen receptor (AR) dependent form situation and treatment of diseases active compound and pharmacologically acceptable salt and ester, and relate to the pharmaceutical composition that contains this compound.The present invention especially discloses the nonsteroidal methane amide that can be used as tissue selective androgen receptor regulator (SARM) and the compound of acyl group hydrazone structure.The compounds of this invention with AR antagonistic activity can be used for treating the patient who needs the androgen receptor antagonists treatment.Especially, AR antagonist of the present invention can be used for treating or preventing cancer, particularly AR dependent form cancer prostate cancer and wherein need other disease of AR antagonistic action for example.
Background of invention
Recent years, the interest of on-steroidal regulator that is used for the steroid receptor of therepic use for exploitation constantly increases.Demonstrate, nonsteroidal part can reach better receptor-selective and better physical chemistry, pharmacokinetics and pharmacology performance.For androgen receptor (AR), used on-steroidal antagonist (antiandrogen) to offset excessive androgenic unwanted effect clinically at present.
Be the initiation of prostate cancer and make progress necessary through the acting male sex hormone of AR.Therefore, the treatment of advanced prostate cancer comprises the androgen-deprivation therapy, for example exenterate testis or utilize gonadotropin releasing hormone (GnRH) agonist, antiandrogen or both hormone regulating and controllings.Although this treatment causes the degeneration of disease at first, all patients can develop into the unmanageable castration resistivity of present treatment late period at last.Castration resistivity prostate cancer (CRPC) is relevant with the AR level that increases.First-generation antiandrogen for example bicalutamide through genetic engineering modified and express in the cell of high AR level and show agonist activity.In vitro and in vivo, the AR of increase shows and makes prostate cancer cell line have the resistance to the androgen antagonist treatment.In order to overcome chemical sproof problem, can in the cell of expressing excessive AR, keep the s-generation antiandrogen of antagonistic action might be used to treat CRPC.
The on-steroidal androgen receptor antagonists is recorded in the for example open EP 100172 of patent, EP1790640, US 6 already; 087; 509, US 6; 673,799, US 7271188, WO 03/057669, WO 2004/099188, WO 2006/133567, WO 2008/124000, WO2009/028543 and WO 2009/055053.
The compound of relevant methane amide structure is recorded in WO 2008/062878.
Summary of the invention
Find that the compound of formula (I) or (I ') is effective androgen receptor (AR) regulator, especially an AR antagonist.The compound of formula (I) or (I ') shows significant high-affinity and strong antagonistic activity to androgen receptor.In addition, in the cell (" cell of AR over-expresses ") of over-expresses AR, The compounds of this invention has from very high until AR antagonistic action completely, only shows minimum agonism simultaneously.The compounds of this invention also suppresses the propagation of prostate cancer cell line effectively.In addition, The compounds of this invention also has the possibility of lower drug-drug interactions, favourable safety performance and enough water-soluble.
Therefore, The compounds of this invention especially can be used as and is used to treat prostate cancer and wherein needs other AR dependent form situation of AR antagonistic action and the medicine of disease.
The invention provides formula (I) compound and the pharmacologically acceptable salt thereof of new methane amide structure:
Figure BDA0000157427790000021
Wherein
R 1Be hydrogen, halogen, cyanic acid, nitro or optional substituted 5-or 6-unit heterocycle;
R 2Be hydrogen, halogen, cyanic acid, nitro, amino, C 1-7Alkyl, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, C 1-7Alkylthio or C 1-7Alkoxyl group;
R 3Be hydrogen, halogen or C 1-7Alkyl,
Or R 2And R 3Form optional substituted 5-or 6-unit's carbocyclic ring or heterocycle with the carbon atom that they connected;
R wherein 1, R 2And R 3In at least two be not hydrogen;
R 4, R 4', R 5, R 6And R 7Be hydrogen, C independently 1-7Alkyl, halo C 1-7Alkyl or hydroxyl C 1-7Alkyl;
Annular atoms E is C or N;
Dotted line is meant optional two keys;
A is a 5-12 unit heterocycle;
B is a 5-unit heterocycle, and wherein the 1-3 in the ring members is the heteroatoms that is selected from N, O and S;
R 8Be hydrogen, hydroxyl, halogen, nitro, amino, cyanic acid, oxo, C 1-7Alkyl, C 1-7Alkoxyl group, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, cyanic acid C 1-7Alkyl, amino C 1-7Alkyl, oxo C 1-7Alkyl, C 1-7Alkoxy C 1-7Alkyl, the amino C of sulfonyloxy methyl 1-7Alkyl, oxyethane C 1-7Alkyl, C 1-7Alkylamino, hydroxyl C 1-7Alkylamino, C 1-7Alkoxy C 1-7Alkylamino, C 1-7Alkylamino C 1-7Alkyl, hydroxyl C 1-7Alkylamino C 1-7Alkyl, oxyimino C 1-7Alkyl, halo C 1-7Alkyl hydroxy C 1-7Alkyl ,-C (O) R 10,-OC (O) R 17,-NH-C (O) R 18Or optional substituted 5-12 unit's carbocyclic ring or heterocycle, all groups all randomly pass through C 1-7Alkylidene group connects base and is connected on the A-ring;
R 9Be hydrogen, halogen, C 1-7Alkyl, oxo, hydroxyl C 1-7Alkyl, oxo C 1-7Alkyl or optional substituted 5 or 6 yuan of carbocyclic rings or heterocycle, all groups all randomly pass through C 1-7Alkylidene group connects base and is connected on the A-ring;
R 10Be hydrogen, hydroxyl, C 1-7Alkyl, hydroxyl C 1-7Alkyl, halo C 1-7Alkyl, C 1-7Alkoxyl group, NR 11R 12Or optional substituted 5-12 unit's carbocyclic ring or heterocycle;
R 11Be hydrogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, amino C 1-7Alkyl, C 1-7Alkylamino C 1-7Alkyl;
R 12Be hydrogen or C 1-7 alkyl;
R 13And R 14Be hydrogen, C independently 1-7Alkyl, halogen, cyanic acid or hydroxyl C 1-7Alkyl;
R 15And R 16Be hydrogen, oxo, sulfo-, C independently 1-7Alkyl or cyanic acid;
R 17Be C 1-7Alkyl, C 1-7Alkoxyl group, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl;
R 18Be C 1-7Alkyl, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl.
One type of preferred formula (I) compound is that wherein B is that the group of formula (1 '), the substituting group of B are R 13And R 14Compound:
Figure BDA0000157427790000041
Wherein Z is O, N, C=O or C=S; X is C or N; Y is C or N; G is that CH, C=O or C=S and M are CH or O; Dotted line is meant optional two keys, asterisk represent to be connected on the ring point and R13 and R14 such as above about formula (I) compound definition.
Another kind of preferred formula (I) compound is that wherein B is that the group of formula (2 '), (3 ') or (4 '), the substituting group of B are the compounds of R13 and R14, they once more such as above about formula (I) compound definition, and the point on the ring represented to be connected in asterisk.
Figure BDA0000157427790000042
Another kind of preferred formula (I) compound is formula (II) compound, wherein R 1, R 2, R 3, R 4, R 4', R 5, R 6, R 7, R 8, R 9, R 13, R 14, A, E, Z, X, Y, G and M such as above about formula (I) compound definition.
Figure BDA0000157427790000051
One type of preferred formula (I) compound is formula (III) compound, wherein R 1, R 2, R 3, R 4, R 4', R 5, R 6, R 7, R 8, R 9, R 13, R 14, A and E such as above about formula (I) compound definition.
Figure BDA0000157427790000052
Another kind of preferred formula (I) compound is formula (IV) compound, wherein R 1, R 2, R 3, R 4, R 4', R 5, R 6, R 7, R 8, R 9, R 13, R 14, A and E such as above about formula (I) compound definition.
Figure BDA0000157427790000053
Another kind of preferred formula (I) compound is formula V compound, wherein R 1, R 2, R 3, R 4, R 4', R 5, R 6, R 7, R 8, R 9, R 13, R 14, A and E such as above about formula (I) compound definition.
Figure BDA0000157427790000061
Another kind of preferred formula (I) compound is formula (VI) compound, wherein R 1Be halogen, methyl, cyanic acid, nitro or trifluoromethyl; R 2Be cyanic acid, halogen or nitro; R 3Be hydrogen, halogen or methyl; R 4Be hydrogen or methyl; R 5Be hydrogen or C 1-3Alkyl; A, R 8And R 9Such as above about formula (I) compound definition.
A kind of preferred formula (VI) compound subclass is R wherein 1Be halogen, R 2Be cyanic acid; R 3Be hydrogen, halogen or methyl; R 4Be hydrogen, R 5Be methyl and A, R 8And R 9As above about the defined compound of formula (I) compound.
On the other hand, the invention provides the methane amide structure and compound acyl group hydrazone structure of formula (I ') and pharmacologically acceptable salt is used for the medicine of prevention or treatment androgen receptor (AR) dependent form illness in preparation purposes thereof:
Figure BDA0000157427790000063
Wherein
R 1Be hydrogen, halogen, cyanic acid, nitro or optional substituted 5-or 6-unit heterocycle;
R 2Be hydrogen, halogen, cyanic acid, nitro, amino, C 1-7Alkyl, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, C 1-7Alkylthio or C 1-7Alkoxyl group;
R 3Be hydrogen, halogen or C 1-7Alkyl,
Or R 2And R 3Form optional substituted 5-or 6-unit's carbocyclic ring or heterocycle with the carbon atom that they connected;
R wherein 1, R 2And R 3In at least 2 be not hydrogen;
R 4, R 4', R 5, R 6And R 7Be hydrogen, C independently 1-7Alkyl, halo C 1-7Alkyl or hydroxyl C 1-7Alkyl;
Annular atoms E is C or N;
D is C or N;
Dotted line is meant optional two keys;
A is a 5-12 unit heterocycle;
B is a 5-unit heterocycle, and wherein the 1-3 in the ring members is the heteroatoms that is selected from N, O and S;
R 8Be hydrogen, hydroxyl, halogen, nitro, amino, cyanic acid, oxo, C 1-7Alkyl, C 1-7Alkoxyl group, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, cyanic acid C 1-7Alkyl, amino C 1-7Alkyl, C 1-7Alkoxy C 1-7Alkyl, the amino C of sulfonyloxy methyl 1-7Alkyl, oxyethane C 1-7Alkyl, C 1-7Alkylamino, hydroxyl C 1-7Alkylamino, C 1-7Alkoxy C 1-7Alkylamino, C 1-7Alkylamino C 1-7Alkyl, hydroxyl C 1-7Alkylamino C 1-7Alkyl, oxyimino C 1-7Alkyl, halo C 1-7Alkyl hydroxy C 1-7Alkyl ,-C (O) R 10,-OC (O) R 17,-NH-C (O) R 18Or optional substituted 5-12 unit's carbocyclic ring or heterocycle, all groups all randomly pass through C 1-7Alkylidene group connects base and is connected on the A-ring;
R 9Be hydrogen, halogen, C 1-7Alkyl, oxo or optional substituted 5 or 6 yuan of carbocyclic rings or heterocycle, all groups all randomly pass through C 1-7Alkylidene group connects base and is connected on the A-ring;
R 10Be hydrogen, hydroxyl, C 1-7Alkyl, hydroxyl C 1-7Alkyl, halo C 1-7Alkyl, C 1-7Alkoxyl group, NR 11R 12Or optional substituted 5-12 unit's carbocyclic ring or heterocycle;
R 11Be hydrogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, amino C 1-7Alkyl, C 1-7Alkylamino C 1-7Alkyl;
R 12Be hydrogen or C 1-7Alkyl;
R 13And R 14Be hydrogen, C independently 1-7Alkyl, halogen, cyanic acid, halo C 1-7Alkyl or hydroxyl C 1-7Alkyl;
R 15And R 16Be hydrogen, oxo, sulfo-, C independently 1-7Alkyl or cyanic acid;
R 17Be C 1-7Alkyl, C 1-7Alkoxyl group, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl;
R 18Be C 1-7Alkyl, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl.
One type of preferred formula (I ') compound is formula (II ') compound, wherein R 1, R 2, R 3, R 4, R 4', R 5, R 6, R 7, R 8, R 9, R 13, R 14, A, E, D, Z, X, Y, G and M such as above about formula (I ') compound definition.
One type of concrete formula (I ') compound is the acyl group hydrazone compound of formula (III '), wherein R 1, R 2, R 3, R 4, R 7, R 8, R 9, R 13, R 14, R 15, R 16, A, B and E such as above about formula (I ') compound definition.
Figure BDA0000157427790000082
Another kind of concrete formula (I ') compound is the acyl group hydrazone compound of formula (IV '), wherein R 1, R 2, R 3, R 4, R 7, R 8, R 9, R 13, R 14, R 15, R 16, A, E, Z, X, Y, G and M such as above about formula (I ') compound definition.
Figure BDA0000157427790000091
Another kind of concrete formula (I ') or (III ') compound are the acyl group hydrazone compounds, and wherein B is the group of formula defined above (2 '), (3 ') or (4 ').
Another kind of preferred compound is the compound of formula (I), (II), (III), (IV), (V), (VI), (I '), (II '), (III ') or (IV '), and wherein A is any one in following groups or its tautomer:
Wherein all above-mentioned rings are all by R defined above 8And R 9Replace.The compound of formula (I), (II), (III), (IV), (V), (V1), (I '), (II '), (III ') or (IV ') preferably, wherein A is any one in group (5 '), (6 '), (7 '), (8 '), (12 '), (20 '), (21 '), (27 ') and (28 ') or its tautomer.A subclass of above preferred compound is R wherein 8Be hydrogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, halogen, pyridyl, pyrazolyl, imidazolyl, furyl ,-C (O) R 10Or-OC (O) R 17A compounds, R wherein 10Be C 1-7Alkyl, R 17Be C 1-7Alkyl and R 9Be hydrogen, halogen or C 1-7Alkyl, and wherein pyridyl, pyrazolyl, imidazolyl, furyl ,-C (O) R 10Or-OC (O) R 17Group can pass through C 1-7Alkylidene group connects base and is connected on the A ring.The compound of preferred above-mentioned subclass is R wherein 1Be halogen, R 2Be cyanic acid; R 3Be hydrogen, halogen or methyl; R 4Be hydrogen, R 5It is the compound of methyl.
Another kind of preferred compound is the compound of formula (I), (I ') or (III '), wherein
Annular atoms E is C;
R 1Be halogen, C 1-7Alkyl, cyanic acid, nitro or halo C 1-7Alkyl;
R 2Be cyanic acid, halogen or nitro;
R 3Be hydrogen, halogen or C 1-7Alkyl;
A is any one in group (5 '), (6 '), (7 '), (8 '), (12 '), (20 '), (21 '), (27 ') and (28 ') or its tautomer;
B is by R 13And R 14The group of substituted formula (2 '), (3 ') or (4 '), said R 13And R 14Be hydrogen;
R 4(and R 4', if be suitable for) be hydrogen or methyl;
R 5Be hydrogen or C 1-7Alkyl;
R 6If (being suitable for) is hydrogen;
R 8Be hydrogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, halogen, oxyimino C 1-7Alkyl, 5 or 6 yuan of heterocycles or-C (O) R 10, R wherein 10Be C 1-7Alkyl, and
R 9Be hydrogen, halogen or C 1-7Alkyl.
The present invention further provides the method for treatment or prevention androgen receptor (AR) dependent form situation, and this method comprises the compound to the formula (I) of the individual administering therapeutic significant quantity that these needs are arranged or (I ').For example, AR dependent form situation to be treated is a cancer, especially for example prostate cancer, benign prostatic hyperplasia, androgenetic alopecia and seat sore of AR dependent form cancer.According to one embodiment of the invention, AR dependent form situation to be treated is a castration resistivity prostate cancer (CRPC).
The present invention also provides the pharmaceutical composition that comprises formula (I) compound and pharmaceutically acceptable carrier.
Detailed Description Of The Invention
The compounds of this invention can through with document in the suitable raw material of the similar various synthetic route utilizations of known method prepare.For example, wherein R 4, R 4', R 6And R 7Be hydrogen and R 1, R 2, R 3, R 5, R 8, R 9, R 13, R 14, R 15, R 16, A, B and E such as above can for example be similar to or prepare according to reaction process 1 about the defined formula of formula (I) compound (I) compound.Some compound that is included in the formula (I) can obtain through the for example oxidation of well-known reactions step, reduction, hydrolysis, acylations, alkylation, amidation, amination and other reactions step through the functional group that transforms other formula (I) compound that obtains according to flow process 1.
Figure BDA0000157427790000121
Flow process 1
R wherein 8Be-C (O) R 10And R 10Be NR 11R 12Or first heterocyclic formula (I) compound of optional substituted 5-12 that is connected on the carbonyl carbon through annular atoms N can suitably prepare (described heterocycle is with " C " expression) according to flow process 2.R 1, R 2, R 3, R 5, R 9, R 13, R 14, R 15, R 16, A, B and E once more such as above about formula (I) compound definition.
Figure BDA0000157427790000131
Flow process 2
B wherein is formula (I) compound of pyrazoles ring (3 ') can suitably utilize flow process 1 or 2 from the midbody compound of formula (16) method preparation.The midbody compound of formula (16) can be suitably according to flow process 3 preparation, wherein R 1, R 2, R 3, R 5, R 6With E such as above about formula (I) compound definition.
Figure BDA0000157427790000141
Flow process 3
The opticity enantiomorph of formula (I) compound or diastereomer can be for example through utilizing suitable opticity raw material to prepare.For example, the opticity enantiomorph of formula (I) compound can utilize the method preparation of flow process 1 or 2 from the opticity midbody of formula (16a).The opticity midbody compound of formula (16a) can be according to flow process 4 or flow process 5 preparation, wherein R 1, R 2, R 3, R 4, R ' 4, R 5, R 6With E such as above about formula (I) compound definition.
Figure BDA0000157427790000142
Flow process 4
Figure BDA0000157427790000151
Flow process 5
In addition, the midbody compound of formula (16) also can be according to flow process 6 preparation, wherein R 1, R 2, R 3, R 4, R ' 4, R 5, R 6With E such as above about formula (I) compound definition and Tr be trityl (trityl group).
Figure BDA0000157427790000152
Flow process 6
Formula (I) compound with optional two keys can be suitably according to flow process 7 preparation, wherein R 1, R 2, R 3, R 5, R 8, R 9, R 13, R 14, R 15, R 16, A, B and E such as above about formula (I) compound definition.
Flow process 7
D wherein be the acyl group hydrazone compound of the formula (I ') of N be can buy or can be for example according to flow process 8 preparation, wherein R 1, R 2, R 3, R 4, R 8, R 9, R 13, R 14, R 15, R 16, A, B and E such as above about formula (I ') compound definition.Some compound that is included in the formula (I ') can obtain through the for example oxidation of well-known reactions step, reduction, hydrolysis, acylations, alkylation, amidation, amination and other reactions step through the functional group that transforms other formula of obtaining according to flow process 8 (I ') compound.
Flow process 8
The raw material of above flow process be can buy or can prepare in accordance with known methods.
Pharmacologically acceptable salt, for example the acid salt with organic and mineral acid is that pharmacy field is known.The nonrestrictive example of these salt comprises muriate, bromide, vitriol, nitrate salt, phosphoric acid salt, sulphonate, formate, tartrate, PHENRAMINE MALEATE, Citrate trianion, benzoate, salicylate and ascorbate salt.Under suitable situation, pharmaceutically acceptable ester can utilize the pharmaceutically acceptable acid pharmacy field routine and the pharmacology performance reservation free form to prepare through known method.The nonrestrictive example of these esters comprises the ester of Fatty Alcohol(C12-C14 and C12-C18) and aromatic alcohol, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec.-butyl, tertiary butyl ester.SULPHOSUCCINIC ACID ESTER and carbonic ether are also within the scope of the invention.
The all possible isotropic substance and the steric isomer that comprise this compound with the definition of following formula (I); Comprise geometrical isomer, for example Z and E isomer (cis and trans-isomer(ide)) and optical isomer; For example diastereomer and enantiomorph, and all prodrug esters, for example SULPHOSUCCINIC ACID ESTER and carbonic ether.In addition, the present invention also comprises individual isomers and any mixture, for example racemic mixture in its scope.
In one embodiment, term " isomer " means the optical isomer that comprises The compounds of this invention.One of ordinary skill in the art would recognize that The compounds of this invention contains at least one chiral centre.Therefore, The compounds of this invention can optically-active form or racemic form existence.Should be understood to, the present invention includes any racemize or optically-active form or its mixture.In one embodiment, The compounds of this invention is pure (R)-isomer.In another kind of embodiment, The compounds of this invention is pure (S)-isomer.In another kind of embodiment, The compounds of this invention is (R) and (S) mixture of isomers.In another kind of embodiment, The compounds of this invention is to comprise the equivalent (R) and (S) racemic mixture of isomer.The compounds of this invention can contain 2 chiral centres.In this case, according to a kind of embodiment of the present invention, The compounds of this invention is pure diastereomer.According to another embodiment of the present invention, The compounds of this invention is the mixture of several kinds of diastereomers.The corresponding isomeric form of individual isomers raw material capable of using obtains, or after making final compound, their separation methods according to routine is separated.For separating optical isomeric body, for example enantiomorph or diastereomer from its mixture, can use conventional method for splitting, for example fractional crystallization.
Term used herein has following implication:
Term used herein " halogen " itself or be meant chlorine, bromine, fluorine or iodine as the part of another group.
Term " C used herein 1-7Alkyl " itself or be meant saturated or unsaturated straight chain, side chain or cyclic group as the part of another group with 1 to 7 carbon atom.C 1-7The representative example of alkyl includes but not limited to, methyl, ethyl, vinyl, n-propyl, sec.-propyl, propenyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, cyclopentyl, cyclohexyl etc.
Term " C 1-7Alkylidene group connects base " be meant saturated or unsaturated straight chain, side chain or cyclic C that 2 groups are linked together 1-7Alkyl chain.C 1-7The instance that alkylidene group connects base is methylene radical (CH 2-) and ethylidene (CH 2-CH 2-) chain.
Term used herein " hydroxyl " itself or be meant-the OH group as the part of another group.
Term used herein " cyanic acid " itself or be meant-the CN group as the part of another group.
Term used herein " hydroxyl C 1-7Alkyl " be meant through C defined herein 1-7Alkyl is hanging at least one hydroxyl defined herein on the parent molecular moiety.Hydroxyl C 1-7The representative example of alkyl includes but not limited to hydroxymethyl, 2,2-dihydroxy ethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 1-methyl isophthalic acid-hydroxyethyl, 1-methyl isophthalic acid-hydroxypropyl etc.
Term used herein " halo C 1-7Alkyl " be meant through C defined herein 1-7Alkyl is hanging at least one halogen defined herein on the parent molecular moiety.Halo C 1-7The representative example of alkyl includes but not limited to methyl fluoride, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl etc.
Term " C used herein 1-7Alkoxyl group " itself or be meant-O-C as the part of another group 1-7Alkyl, wherein C 1-7Alkyl such as defined herein.C 1-7The representative example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy etc.
Term " C used herein 1-7Alkylthio " be meant-S-C 1-7Alkyl, wherein C 1-7Alkyl such as defined herein.C 1-7The representative example of alkylthio includes but not limited to methylthio group (SCH 3), ethylmercapto group etc.
Term " oxo " be meant two key groups of connecting as substituting group (=O).
Term " sulfo-" be meant two key groups of connecting as substituting group (=S).
Term used herein " amino " itself or be meant-NH as the part of another group 2Group.
Term " C used herein 1-7Acyl group " itself or be meant C as the part of another group 1-7Alkyl-carbonyl, the example comprise ethanoyl, propionyl group, sec.-propyl acyl group, butyryl radicals, secondary butyryl radicals, uncle-butyryl radicals and pentanoyl.
Term used herein " amino C 1-7Alkyl " be meant through C defined herein 1-7Alkyl is hanging at least one amino defined herein on the parent molecular moiety.Amino C 1-7The representative example of alkyl includes but not limited to amino methyl, 2-amino-ethyl, 1-amino-ethyl, 2,2-diamino ethyl, 3-aminopropyl, 2-aminopropyl, the amino butyl of 4-, 1-methyl isophthalic acid-amino-ethyl etc.
Term " C used herein 1-7Alkylamino " itself or be meant through amino defined herein as the part of another group and be hanging to one or 2 C defined herein on the parent molecular moiety 1-7Alkyl.C 1-7The representative example of alkylamino includes but not limited to that methylamino, ethylamino, propyl group are amino, butyl is amino, dimethylamino, diethylamino, N-ethyl-N-methylamino etc.
Term " C used herein 1-7Alkylamino C 1-7Alkyl " be meant through C defined herein 1-7Alkyl is hanging to the C defined herein on the parent molecular moiety 1-7Alkylamino.C 1-7Alkylamino C 1-7The representative example of alkyl includes but not limited to N, N-dimethylaminomethyl, N, N-diethylamino methyl, N-methylamino ethyl, N-methylamino propyl group, N-ethyl-N-methylamino methyl etc.
Term used herein " hydroxyl C 1-7Alkylamino C 1-7Alkyl " be meant through C defined herein 1-7Alkyl is hanging to the hydroxyl C defined herein on the parent molecular moiety 1-7Alkylamino.C 1-7Alkylamino C 1-7The representative example of alkyl includes but not limited to N-hydroxymethyl amino-ethyl, N-ethyl-N-hydroxymethyl amino methyl etc.
Term " C used herein 1-7Alkoxy C 1-7Alkyl " be meant through C defined herein 1-7Alkyl is hanging at least one C defined herein on the parent molecular moiety 1-7Alkoxyl group.C 1-7Alkoxy C 1-7The representative example of alkyl includes but not limited to methoxymethyl, ethoxyl methyl, 2-methoxy ethyl, 2-ethoxyethyl group, 3,3-dimethoxy propyl group, 2,4-dimethoxy butyl etc.
Term used herein " imino-C 1-7Alkyl " be meant through C defined herein 1-7Alkyl be hanging at least one imino-on the parent molecular moiety (=NH).
Term used herein " oxyimino C 1-7Alkyl " be meant through C defined herein 1-7Alkyl is hanging on the parent molecular moiety=the N-OH group.
Term used herein " 5-or 6-unit heterocycle " is meant saturated, fractional saturation or the aromatic ring with 5 or 6 annular atomses, and the atom of 1-3 wherein is the heteroatoms that is selected from N, O and S.5-or 6-unit heterocyclic representative example include but not limited to pyrazolyl, furyl, piperazinyl, piperidyl, pyridyl ring etc.
Term used herein " 5-or 6-unit carbocyclic ring " is meant saturated, fractional saturation or the aromatic ring that only has 5 or 6 annular atomses being made up of carbon atom.5-or 6-unit isocyclic representative example include but not limited to phenyl and cyclohexyl ring etc.
Term used herein " 5-12 unit heterocycle " is meant monocycle or two ring fillings, fractional saturation or aromatic ring with 5 to 12 annular atomses, and wherein 1-4 atom is the heteroatoms that is selected from N, O and S.5-12 unit heterocyclic representative example includes but not limited to pyrazolyl, furyl, piperazinyl, piperidyl, pyridyl, morpholinyl, pyrazinyl, indazolyl, imidazolyl, pyrazolo [1,5-a] pyrimidyl, different
Figure BDA0000157427790000201
azoles base and thiazole basic ring etc.
Term used herein " 5-12 unit carbocyclic ring " is meant saturated, fractional saturation or the aromatic ring with 5-12 annular atoms that only is made up of carbon atom.5-12 unit isocyclic representative example includes but not limited to phenyl, naphthyl and cyclohexyl ring etc.
The term that used herein and various residues are connected " optional substituted " is meant halogenic substituent for example fluorine, chlorine, bromine, iodine, or C 1-7Alkyl, hydroxyl, amino, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, C 1-7Alkoxyl group, C 1-C 7Acyl group, C 1-7Alkylamino, amino C 1-7Alkyl, methyl sulphonyl, nitro, cyanic acid, mercaptan or 5-or 6-unit's carbocyclic ring or heterocyclic substituent.Preferred substituted is halogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, C 1-C 7Acyl group, pyridyl, morpholinyl and benzyl substituting group.
" optional substituted " group can contain 1 to 3, preferred 1 or 2,1 above-mentioned substituting group most preferably.
Preferred formula (I) examples for compounds comprises
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-(morpholine-4-carbonyl)-1H-pyrazoles-5-methane amide;
(S/R)-N-(1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-yl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide;
(S)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide;
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide;
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000211
azoles-3-methane amide;
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000212
azoles-3-methane amide;
N-(2-(3-(3,4-dicyano phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide;
(R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide;
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide;
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide;
(R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide;
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide;
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide;
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide;
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide;
The 3-tertiary butyl-N-(1-(5-(4-cyanic acid-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide;
The 3-tertiary butyl-N-(2-(5-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide;
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide;
(S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide;
(R)-N-(1-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide;
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide;
N-((S)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide;
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methyl different azoles-3-methane amide;
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide;
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-formamide;
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide;
(R)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide;
(R)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide;
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-methylthiazol-4-yl)-1H-pyrazole-3-formamide;
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-methyl isophthalic acid; 2,4-two
Figure BDA0000157427790000231
azoles-5-methane amide;
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-morpholino thiazole-4-carboxamide;
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-pyrazoles-4-yl) thiazole-4-carboxamide;
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid H-imidazoles-4-methane amide;
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different
Figure BDA0000157427790000232
azoles-3-methane amide;
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-ethyl-1; 2,4-two
Figure BDA0000157427790000233
azoles-5-methane amide;
N-((S)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide;
(R)-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-2-(cyano methyl) thiazole-4-carboxamide;
(S)-N-{1-[3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid H-imidazoles-4-methane amide;
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyrimidine-2-methane amide;
(S)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide;
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2,4,6, the 7-tetrahydropyrans is [4,3-c] pyrazole-3-formamide also.
Can The compounds of this invention be used to the patient with the treatment significant quantity; Said treatment significant quantity depends on patient's age, body weight, race, patient's situation, situation, route of administration and used male sex hormone (AR) regulator to be treated, and normally every day about 0.1 to about 5000mg, preferred about 1 is to about 2000mg.Utilize principle known in the art to be mixed with formulation The compounds of this invention.Can directly give the patient with itself, or give the patient with the combined form of suitable pharmaceutical vehicle with tablet, granula, capsule, suppository, emulsion, suspensoid or solution.Selecting the suitable composition that is used for compsn is those of ordinary skills' routine selection.It is obvious that, also can use appropriate carriers, solvent, gel formation composition, dispersion liquid to form composition, inhibitor, tinting material, sweeting agent, humidification compound and the normally used composition of other this technical field.To contain composition of active components through intestines or parenteral admin, oral route is preferred mode.The content of active compound is about 0.5 to 100%, preferred about 1 to about 85% of total composition weight in the compsn.
Explain the present invention in more detail through following embodiment.Embodiment only is used for the purpose of explaining and can limit the defined scope of the present invention of claim.
Experiment
Experiment 1
Measure the AR binding affinity (Ki) of testing compound.
With in the hAR/HEK293 cell to the IC of people AR 50Value (nM) is measured the AR antagonistic action of testing compound.
The AR agonism of testing compound in the hAR/HEK293 of AR over-expresses cell measured with the active % form of the testosterone inductive AR under the 10 μ M concentration.
Measured the IC of testing compound inhibition mibolerone inductive VCaP cell proliferation 50Value.
Bicalutamide is used as the reference compound in measuring.
Method
Androgen receptor combines test
The androgen receptor of testing compound (AR) binding affinity is studied (Schilling K. and Liao S., The Prostate, 1984 through CBA in the prostatic cytosol product of belly that derives from the castrating rat; 5 (6): 581-588).Cytosol preparation and 1nM [3H] mibolerone are hatched with the testing compound that concentration increases gradually.In order to confirm non-specific binding, carry out parallel hatching with excessive unlabelled testosterone.After hatching, bonded is separated through handling with the charcoal suspension-s that scribbles DEXTRAN 500.000 with the free steroid.The bonded radioactivity is through counting to confirm to supernatant level branch in scintillation solution.Radioactivity utilizes the Microbeta telltale to measure.All data points are all carried out in quadruplicate.For the rat androgen receptor, the dissociation constant of [3H] mibolerone is measured (Isomaa V. etc., Endocrinology, 1982 according to described method basically through the prostatic saturated combination test of the belly that derives from the castrating rat; 111 (3): 833-843).
The analysis of data
In order to analyze saturated binding affinity, applying unit point combines equation (hyperbolic line)
Figure BDA0000157427790000251
Wherein
B Max=maximum specificity combines
The Kd=equilibrium dissociation constant
The concentration of X=radioligand
Equilibrium dissociation constant (Ki) utilizes Cheng and Prusoff equation to calculate:
Figure BDA0000157427790000261
Wherein
The concentration of [radioligand]=radioligand
K d=radioligand is to the dissociation constant of acceptor
The IC that IC50=measures in competitive radioligand combines to test 50Value
The AR antagonistic action
Testing compound is measured in human embryo kidney (HEK) (HEK293) cell (hAR/HEK293 cell) of the expression vector stable transfection of using coding total length people AR and male sex hormone responsiveness luciferase reporter gene tectosome through the reporter gene test the antagonistic action of AR.In order to confirm the antagonistic action to hAR, the testing compound that cell is increased progressively with concentration simultaneously and the testosterone (normally 0.45nM) of inferior peak concentration are handled.Final DMSO concentration is 1%.All testing compounds are studied in triplicate.Cell was hatched 24 hours, use Luciferase Assay System (Promega Corporation) to measure uciferase activity then.
Testing compound is measured in the HEK293 cell of the expression vector stable transfection of usefulness coding total length people AR and male sex hormone responsiveness luciferase reporter gene tectosome through the reporter gene test at the intracellular agonism of AR over-expresses.Select the clone who expresses high-level androgen receptor (higher more than 5 times) to study intracellular agonism in the AR over-expresses than the AR level in the AR-HEK293 cell.In order to confirm agonism, cell is handled with the testing compound that concentration increases progressively.Final DMSO concentration is 1%.Testing compound is studied in triplicate, and measured uciferase activity according to the method described above.
Cell proliferation test
Testing compound suppresses the ability of prostate cancer cell growth and utilizes the responsive VCaP prostate cancer cell line of male sex hormone to study through the restraining effect of measuring cell proliferation.Cell is inoculated into the appropriate culture medium (do not contain phenol red RPMI-1640, be supplemented with extractive FBS of 10% charcoal and 4mM Glutamax+100IU penicillium mould, the 100IU Streptomycin sulphate) that is arranged in 96 orifice plates with the density of 50000 cells/well.Made cell attachment 2-3 days and used subsequently testing compound to be handled 4-5 days down in the existence of mibolerone (can inducing cell the inferior maximum concentration that increases of propagation, normally 0.1nM).Utilize WST-1 cell proliferation test (Roche) to measure the propagation of cell.
Table 1.AR binding affinity, AR antagonistic action, in the intracellular AR agonism of AR over-expresses and the restraining effect of VCaP cell proliferation
Figure BDA0000157427790000271
Embodiment:
The end product of the following example is with the prepare of non-enantiomer mixture, except as otherwise noted.
Embodiment 1
5-(piperazine-1-carbonyl)-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides is 2-(3, the 4-dichlorophenyl)-5-((E)-2-nitroethylene base) furans a)
((2.0ml, 1.42g 24.0mmol) handle with n-propyl amine down at 0 ℃ under nitrogen atmosphere for 1.4ml, 1.46g, methyl alcohol 24.3mmol) (3.5ml) solution with the acetate that is stirring.The n-propyl ammonium acetate solution that forms was stirred 5 minutes down at 0 ℃, and (10.04g, (6.8ml, 7.61g is 124.7mmol) in the solution for Nitromethane 99Min. 41.6mmol) under 0 ℃, to be added drop-wise to 5-(3, the 4-dichlorophenyl) furfural that is stirring then.The mixture that forms was stirred 30 minutes down at 0 ℃.Remove cooling bath then and at room temperature continue and stir.Each 10ml THF that adds adds 5 times.Evaporate THF after the stirred overnight and add entry.With solid filtering, water and heptane wash obtain 11.46g 2-(3, the 4-dichlorophenyl)-5-((E)-2-nitroethylene base) furans. 1H?NMR(400MHz，DMSO-d 6)：7.38(1H，d)，7.43(1H，d)，7.76(1H，d)，7.95(1H，dd)，8.03(1H，d)，8.19(1H，d)，8.31(1H，d)。
B) 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamine hydrochloride
(5.73g 20.2mmol) is dissolved in the mixture of exsiccant methyl alcohol (90ml) and exsiccant ETHYLE ACETATE (70ml) with 2-(3, the 4-dichlorophenyl)-5-((E)-2-nitroethylene base) furans.Add 14.3ml10w-%HCl-methyl alcohol and 2.4g 10% palladium carbon then.With about 4 hours of 2-(3, the 4-dichlorophenyl)-5-((E)-2-nitroethylene base) furans hydrogenation at room temperature under 3atm.Catalyzer filtered through remove.Removal of solvent under reduced pressure obtains crude product, and it through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2/ MeOH (98: 2-80: 20) as the gradient elution agent. 1H NMR (400MHz, DMSO-d 6): 3.04 (2H, m), 3.14 (2H, m), 6.43 (1H, d), 7.07 (1H, d), 7.67 (2H, s), 7.93 (1H, s), 8.19 (3H, wide s).
C) 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical }-1H-pyrazoles-3-formic acid
With 3, (8.02g 46.1mmol) is dissolved in the mixture of exsiccant DMF (35ml), exsiccant DCM (35ml) and DIPEA (7.9ml) to 5-pyrazoles dioctyl phthalate monohydrate.At room temperature add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 3.37g, 17.6mmol), HOBt (2.28g, 16.9mmol) and DIPEA (3ml, 2.23g, 17.3mmol).Solution was mixed 10 minutes.((3.46g 11.8mmol) is added drop-wise in the solution ethylamine hydrochloride 2-of mixture 11.5mmol) [5-(3, the 4-dichlorophenyl) furans-2-yl] for 2.0ml, 1.48g at room temperature will to be dissolved in exsiccant DCM (35ml) and DIPEA then.Add entry after the stirred overnight.Product is used ethyl acetate extraction.Organic phase is used water washing, dry and evaporation.Through purification by flash chromatography, utilize DCM crude product as eluent.Product is developed with hot methanol. 1H NMR (400MHz, DMSO-d 6): 2.95 (2H, t), 3.56 (2H, m), 6.33 (1H, d), 7.01 (1H, d), about 7.03 (1H, wide s), 7.61 (1H, distored dd), 7.63 (1H, distored d), 7.83 (1H, d), about 8.45 (1H, wide s), about 14.05 (1H, wide s).
D) 5-(piperazine-1-carbonyl)-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
With 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical }-(0.30g 0.76mmol) is dissolved in the mixture of exsiccant DMF (3ml) and exsiccant DCM (3ml) to 1H-pyrazoles-3-formic acid.At room temperature add EDCI (0.22g, 1.2mmol), HOBt (0.16g, 1.2mmol) and DIPEA (0.2ml, 0.15g, 1.2mmol).Stir that (0.10g, exsiccant DCM (2ml) solution 1.2mmol) at room temperature is added drop-wise in the solution with piperazine after 15 minutes.Then solution stirring is spent the night.Add entry and product is used ethyl acetate extraction.With salt solution and water washing, drying is also evaporated with organic phase.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (95: 5-50: 50).Carry out purifying through flash chromatography once more, utilize CH 2Cl 2-MeOH (9: 1) is as eluent. 1H NMR (400MHz, CDCl 3): 2.94 (4H, m), 3.01 (2H, t), 3.77 (2H, q), about 3.8 (4H, m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s), 7.21 (1H, wide s), 7.40 (1H, distored d), 7.43 (1H, distored dd), 7.75 (1H, d).
Embodiment 2
5-[4-(2-hydroxyethyl) piperidines-1-carbonyl]-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound according to the described method of previous embodiment with 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical-1H-pyrazoles-3-formic acid and 4-piperidines ethanol prepares as raw material.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-95: 5). 1H NMR (400MHz, CDCl 3): 1.27 (3H, m), 1.57 (2H, m), 1.85 (3H, m), 2.81 (1H, m), 3.01 (2H; T), about 3.21 (1H, m), 3.76 (4H, m), about 4.41 (1H, m), about 4.67 (1H, m); 6.20 (1H, d), 6.59 (1H, d), 7.02 (1H, s), 7.29 (1H, wide s); (7.40 1H, distored d), 7.43 (1H, distored dd), 7.75 (1H, d), 11.4 (1H, wide s).
Embodiment 3
5-(4-hydroxy piperidine-1-carbonyl)-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound utilizes 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical according to embodiment 1 described method }-1H-pyrazoles-3-formic acid and 4-hydroxy piperidine prepare as raw material.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH (95: 5) is as eluent. 1H NMR (400MHz, CDCl 3): 1.62 (1H, d), 1.65 (2H, m), 1.95 (2H, m), 3.00 (2H, t); About 3.57 (2H, m), 3.77 (2H, q), about 4.1 (3H, m), 6.20 (1H, d); 6.58 (1H, d), 7.03 (1H, s), about 7.6 (1H, wide s), 7.40 (1H; Distored d), 7.43 (1H, distored dd), 7.74 (1H, d), 11.6 (1H, wide s).
Embodiment 4
5-[4-(2-hydroxyethyl) piperazine-1-carbonyl]-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound utilizes 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical according to embodiment 1 described method }-1H-pyrazoles-3-formic acid and 1-(2-hydroxyethyl) piperazine prepare as raw material.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-90: 10). 1H NMR (400MHz, DMSO-d 6): 2.40-2.44 (6H, m), 2.95 (2H, t), about 3.5-3.7 (6H, m), about 3.82 (2H; M), 4.41 (1H, t), 6.33 (1H, d), 7.01 (1H, d); About 7.05 (1H, wide s), 7.59 (1H, distored dd), 7.63 (1H, distored d); 7.84 (1H, d), about 8.59 (1H, wide s), 13.9 (1H, wide s).
Embodiment 5
5-(4-ethanoyl piperazine-1-carbonyl)-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound utilizes 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical according to embodiment 1 described method }-1H-pyrazoles-3-formic acid and 1-ethanoyl piperazine prepare as raw material.Crude product is at room temperature used CH 2Cl 2Development obtains product. 1H NMR (400MHz, CDCl 3): 2.15 (3H, s), 3.01 (2H, t), 3.58 (2H, m), 3.72 (2H, m), 3.78 (2H, q), 3.84 (4H, m), 6.21 (1H, d), 6.59 (1H, d), 7.04 (1H, s), about 7.28 (1H, wide s), 7.41 (2H, m), 7.74 (1H, s), 11.35 (1H, wide s).
Embodiment 6
5-(4-morpholine-4-phenylpiperidines-1-carbonyl)-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound utilizes 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical according to embodiment 1 described method }-1H-pyrazoles-3-formic acid and 4-morpholino piperidines prepare as raw material.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-96: 4). 1H NMR (400MHz, DMSO-d 6): about 1.32 (2H, m), about 1.82 (2H, m), 2.45-2.47 (5H, m), about 2.78 (1H, m); 2.95 (2H, t), about 3.11 (1H, m), 3.55-3.57 (6H, m), about 4.45 (1H, m); 6.34 (1H, d), 7.02 (1H, d), about 7.03 (1H, wide s), 7.59 (1H, distored dd); (7.63 1H, distored d), 7.84 (1H, d), 8.6 (1H, wide s), 13.9 (1H, wide s).
Embodiment 7
5-[4-(1-hydroxyethyl) piperidines-1-carbonyl]-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
A) 1-(pyridin-4-yl) ethanol
To the 4-acetylpyridine that is stirring (2.50g, add in methyl alcohol 20.6mmol) (25ml) solution in batches Peng Qinghuana (1.56g, 41.2mmol).At room temperature add entry and mixture vacuum-evaporation is extremely dried after the stirred overnight.In product, add ETHYLE ACETATE.Evaporating solvent obtains the 2.53g title compound. 1H?NMR(400MHz，DMSO-d 6)：1.32(3H，d)，4.69-4.75(1H，m)，5.38(1H，d)，7.34(2H，d)，8.49(2H，d)。
B) 1-(piperidin-4-yl) ethanol
With 1-(pyridin-4-yl) ethanol (2.53g, 20.5mmol) be dissolved in acetate (20ml) and palladous oxide (IV) (0.19g) in the presence of in 1atm hydrogenation under room temperature.With catalyzer filter through remove and the vacuum concentration of will filtrating to obtain crude product 1-(pyridin-4-yl) ethanol of acetate form, it is developed with ETHYLE ACETATE.The aqueous solution of acetate is alkalized (pH＞10) with sodium hydroxide, then 1-(pyridin-4-yl) alcohol extraction of alkali form is gone into ETHYLE ACETATE.With the extraction liquid vacuum concentration. 1H NMR (400MHz, DMSO-d 6): 1.00 (3H, d), 0.94-1.11 (2H, m), 1.14-1.23 (1H, m), 1.44 (1H, m), 1.66 (1H, m), 2.37 (2H, m), 2.91 (2H, m), 3.30 (1H, quintet), 4.23 (1H, wide s).
C) 5-[4-(1-hydroxyethyl) piperidines-1-carbonyl]-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound utilizes 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical according to embodiment 1 described method }-1H-pyrazoles-3-formic acid and 1-(piperidin-4-yl) ethanol prepares as raw material.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-90: 10). 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 1.30-1.41 (3H, m), 1.62 (1H, m), 1.77 (1H, m), 2.00 (1H, m); About 2.78 (1H, m), 3.01 (2H, t), about 3.18 (1H, m), about 3.64 (1H, m), 3.77 (2H, q); About 4.48 (1H, m), about 4.75 (1H, m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s); About 7.28 (1H, wide s), 7.40 (1H, distored d), 7.43 (1H, distored dd), 7.75 (1H, d), 11.44 (1H, wide s).
Embodiment 8
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-(morpholine-4-carbonyl)-1H-pyrazoles-5-methane amide
This title compound utilizes morpholine and 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical according to embodiment 1 described method }-1H-pyrazoles-3-formic acid prepares as raw material.Crude product is passed through chromatogram purification (CombiFlash, first silicagel column, eluent: 0-10%MeOH/DCM; 2 NdPost C-18RP, eluent: 0-100%MeCN/ water) obtain 505mg (17%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.95(t，1H)，3.56(q，1H)，3.62(br?s，6H)，3.90(br?s，2H)，6.34(d，1H)，7.02(d，1H)，7.08(s，1H)，7.62(m，2H)，7.85(d，1H)，8.61(s，1H)，13.94(s，1H)。
Embodiment 9
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-(4-N-METHYL PIPERAZINE-1-carbonyl)-1H-pyrazoles-5-methane amide
This title compound according to embodiment 1 described method with 1-N-METHYL PIPERAZINE and 5-{2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamino formyl radical-1H-pyrazoles-3-formic acid prepares as raw material.Crude product is also obtained 1.06g (35%) title compound with the crystallization of DCM/ heptane through chromatogram purification (CombiFlash, silicagel column, eluent 0-10%MeOH/DCM). 1H-NMR(400MHz；d6-DMSO)：δ2.19(s，3H)，2.33(br?s，4H)，2.95(t，2H)，3.56(q，2H)，3.62(brs，2H)，3.85(br?s，2H)，6.34(d，1H)，7.02(d，1H)，7.07(br?s，1H)，7.60(dd，1H)，7.63(d，1H)，7.84(d，1H)，8.61(s，1H)，13.92(s，1H)。
Embodiment 10
5-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethylamino formyl radical) pyrazine-2-formic acid
With pyrazine-2,5-dioctyl phthalate (0.58g; 3.42mmol), anhydrous HOBt (0.69g; 5.13mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.98g: 5.13mmol) join among the 5ml DCM.With 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethylamine hydrochloride (1.0g; 3.42mmol) and DIPEA (0.89ml; 5.13mmol) be dissolved in 5ml DCM and be added drop-wise in the aforementioned mixture.With the reaction mixture stirred overnight, add pyrazine-2 then, 5-dioctyl phthalate (0.58g; 1.59mmol) and DIPEA (0.60ml; 3.42mmol) and mixture stirred 5 hours once more.Add anhydrous HOBt (0.69g once more; 5.13mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.98g: 5.13mmol) and DIPEA (0.89ml; 5.13mmol) accomplish to drive reaction.After the stirred overnight with mixture with 20ml DCM dilution and use the 3x10ml water washing.Organic phase is used Na 2SO 4Drying is filtered and can be used without being further purified.
Embodiment 11
N-2-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-N-5-(2-hydroxyethyl) pyrazine-2, the 5-diformamide
With 5-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethylamino formyl radical) pyrazine-2-formic acid (0.12g; 0.30mmol), anhydrous HOBt (0.15g; 1.1mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.085g: 0.44mmol) and DIPEA (0.077ml; 0.44mmol) be dissolved in 2.5ml DCM.In this solution, add 2-monoethanolamine (0.018ml; 0.3ml) 2.5mlDCM solution and with the mixture stirred overnight.With mixture with 10ml DCM dilution and use the 3x5ml water washing.Then water is extracted with EtOAc, organic phase is used Na 2SO 4Drying filters and is evaporated to dried.Product is used purification by flash chromatography.Level branch by merging obtains the 6mg product. 1H-NMR(400MHz；d6-DMSO)：δ3.01(t，2H)，3.38-3.43(m，2H)，3.52-3.57(m，2H)，3.64-3.69(m，2H)，4.81(t，1H)，6.36(d，1H)，7.02(d，1H)，7.58-7.64(m，2H)，7.80(d，1H)，8.91-8.94(t，1H)，9.19(d，1H)，9.21(d，1H)，9.26-9.29(t，1H)。
Embodiment 12
1,5-dimethyl--1H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
With 1, (100mg 0.71mmol) is dissolved in exsiccant DMF (2ml) to 5-dimethyl--1H-pyrazoles-3-formic acid.At room temperature add EDCl (205mg, 1.1mmol), HOBt (145mg, 1.1mmol) and DIPEA (0.19ml, 141mg, 1.1mmol).With solution stirring 30 minutes.((313mg 1.1mmol) joins in the solution ethylamine hydrochloride 2-of mixture 1.1mmol) [5-(3, the 4-dichlorophenyl) furans-2-yl] for 0.19ml, 141mg at room temperature will to be dissolved in exsiccant DMF (4ml) and DIPEA then.Add entry after the stirred overnight.Product is used ethyl acetate extraction.Organic phase is used water washing, dry and evaporation.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-95: 5).Carry out purifying through flash chromatography once more, use CH 2Cl 2-MeOH is as gradient elution agent (100: 0-99.7: 0.3).Product is at room temperature used heptane-CH 2Cl 2Development. 1H NMR (400MHz, DMSO-d 6): 2.26 (3H, s), 2.92 (2H, t), 3.52 (2H, m), 3.76 (3H, s), 6.31 (1H, d), 6.38 (1H, s), 7.01 (1H, d), 7.60 (1H, distored dd), 7.64 (1H, distored d), 7.83 (1H, d), 8.09 (1H, t).
Embodiment 13
5-furans-2-base-1-phenyl-1H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound prepares with 5-(2-furyl)-1-phenyl-1H-pyrazoles-3-formic acid and 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamine hydrochloride according to embodiment 12 described methods.Crude product through purification by flash chromatography twice, is at first utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-99: 1).And then carry out purifying through flash chromatography, utilize heptane/EtOAc (8: 2) as eluent. 1H NMR (400MHz, DMSO-d 6): 2.96 (2H, t), 3.58 (2H, m), 6.16 (1H, d), 6.34 (1H, d), 6.51 (1H; Dd), 7.01 (1H, d), 7.07 (1H, s), 7.45-7.48 (2H, m), 7.54-7.56 (4H, m); (7.61 1H, distored dd), 7.73 (1H, d), 7.84 (1H, d), 8.49 (1H, t 3J=5.9Hz).
Embodiment 14
1-methyl isophthalic acid H-indazole-3-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound prepares as raw material with N-methylindazole-3-formic acid and 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamine hydrochloride according to embodiment 12 described methods.Through purification by flash chromatography, utilize heptane/EtOAc crude product as gradient elution agent (9: 1-8: 2). 1H?NMR(400MHz，DMSO-d 6)：3.00(2H，t)，3.64(2H，m)，4.12(3H，s)，6.36(1H，d)，7.01(1H，d)，7.26(1H，m)，7.46(1H，m)，7.600(1H，s)，7.602(1H，s)，7.72(1H，d)，7.83(1H，s)，8.16(1H，d)，8.48(1H，t)。
Embodiment 15
1H-imidazoles-4-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
This title compound prepares as raw material with 4-imidazole formic acid and 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamine hydrochloride according to embodiment 12 described methods.Crude product through purification by flash chromatography, is utilized CH 2Cl 2/ MeOH is as gradient elution agent (100: 0-99.6: 0.4).Product is developed with ETHYLE ACETATE. 1H NMR (400MHz, DMSO-d 6): 2.93 (2H, t), 3.55 (2H, m), 6.33 (1H, d), 7.01 (1H, d), 7.59 (1H, s), 7.63 (2H, s), 7.71 (1H, s), 7.87 (1H, s), 8.05 (1H, wide s), 12.43 (1H, wide s).
Embodiment 16
2-methyl isophthalic acid H-imidazoles-4-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } amide hydrochloride
This title compound prepares as raw material with 2-methyl isophthalic acid H-imidazoles-4-formic acid and 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethylamine hydrochloride according to embodiment 12 described methods.Crude product through purification by flash chromatography, is utilized CH 2Cl 2/ MeOH is as gradient elution agent (100: 0-97: 3).Product is dissolved in DCM, adds the product filtration of the hydrochloride form of separating out with the saturated ETHYLE ACETATE of hydrogenchloride and with deposition.Use the MeOH/EtOAc recrystallization.HCl salt: 1H NMR (400MHz, MeOH-d 4): 2.62 (3H, s), 3.02 (1H, t), 3.69 (1H, t), 6.26 (1H, d), 6.76 (1H, d), 7.49 (1H, distored d), 6.53 (1H, distored dd), 7.71 (1H, d), 7.82 (1H, s).
Embodiment 17
1H-indazole-3-formic acid { 2-[5-(3, the 4-dichlorophenyl)-furans-2-yl]-ethyl }-acid amides
A) (E)-2-(5-(3, the 4-dichlorophenyl) furans-2-yl) vinyl-amine
To the 5-that is stirring (3, the 4-dichlorophenyl) furfural (1.18g, add in acetate 4.89mmol) (30ml) solution Nitromethane 99Min. (0.535ml, 9.78mmol) and ammonium acetate (1.13g, 14.7mmol).Reaction mixture was heated 4.5 hours down at 80 ℃.The refrigerative reaction mixture is poured on frozen water (30ml) goes up and formed throw out is filtered, obtain 1.15g (83%) title compound with water washing and vacuum-drying. 1H-NMR(400MHz；d6-DMSO)：δ7.37(d，1H)，7.43(d，1H)，7.76(d，1H)，7.95(dd，1H)，8.03(d，1H)，8.19(d，1H)，8.31(d，1H)。
B) 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethamine
(0.939g descends THF (20ml) solution that slowly adds (E)-2-(5-(3, the 4-dichlorophenyl) furans-2-yl) vinyl-amine at 0 ℃ in THF 24.8mmol) (20ml) suspension-s under nitrogen to lithium hydride.Reaction mixture was at room temperature stirred 1 hour.Some methyl alcohol are slowly joined in the mixture, add entry then.Extract (3x) with the mixture evaporation and with solid residue with EtOAc.The EtOAc level that merges is divided with 2M NaOH and brine wash.Organic phase is used Na 2SO 4Drying, evaporation is also passed through chromatogram purification (CombiFlash, silicagel column, eluent: 10-20%MeOH/DCM) obtain 227mg (11%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.74(t，2H)，2.85(t，2H)，6.29(d，1H)，7.03(d，1H)，7.62(dd，1H)，7.63(d，1H)，7.88(d，1H)。
C) 1H-indazole-3-formic acid { 2-[5-(3, the 4-dichlorophenyl)-furans-2-yl]-ethyl }-acid amides
With indazole-3-formic acid (30mg; 0.182mmol), DCC (56mg, 0.273mmol) and DMAP (2mg) be dissolved in DCM: DMF (1: 1,4ml).(46mg is 0.182mmol) and with reaction mixture stirred overnight at room temperature to add 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethamine.Add DCM (30ml) and with organic layer with water washing (3x15ml).The organic phase that merges is used Na 2SO 4Drying, evaporation is also passed through chromatogram purification (silicagel column, eluent: 1%MeOH/DCM) obtain 25mg (34%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ3.00(t，2H)，3.63(q，2H)，6.37(d，1H)，7.02(d，1H)，7.23(t，1H)，7.41(t，1H)，7.60(d，1H)，7.61(d，2H)，7.85(d，1H)，8.16(d，1H)，8.54(d，1H)，13.56(s，1H)。
Embodiment 18
The 5-tertiary butyl-2H-pyrazoles-3-formic acid { 2-[5-(3, the 4-dichlorophenyl)-furans-2-yl]-ethyl }-acid amides
Title compound is synthetic as raw material with the 5-tertiary butyl-2H-pyrazoles-3-formic acid and 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethamine according to the method for embodiment 17.Crude product is passed through chromatogram purification (silicagel column, eluent: 3%MeOH/DCM) obtain 53mg (33%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.27(s，9H)，2.97(t，2H)，3.54(q，2H)，6.33(m，1H)，6.39(br?s，1H)，7.02(d，1H)，7.62(m，2H)，7.86(d，1H)，8.20(s，1H)，12.88(s，1H)。
Embodiment 19
The 3-tertiary butyl-N-(1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) (E)-1-(5-(3, the 4-dichlorophenyl) furans-2-yl) third-1-alkene-2-amine
To the 5-that is stirring (3, the 4-dichlorophenyl) furfural (1.21g, add in acetate 5.0mmol) (15ml) solution nitroethane (0.720ml, 10.0mmol) and ammonium acetate (1.16g, 15.0mmol).With mixture 80 ℃ of following stirred overnight.Reaction mixture is poured in the frozen water.The throw out that forms is filtered, obtain 1.38g (93%) title compound with water washing and vacuum-drying. 1H-NMR(400MHz；d6-DMSO)：δ2.62(s，3H)，7.37(d，1H)，7.46(d，1H)，7.79(m，2H)，7.98(s，1H)，8.09(d，1H)。
B) 1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-amine hydrochlorate
(2.72g 9.12mmol) adds 10%Pd/C (1.09g) in the solution in the MeOH (32ml) of MeOH (135ml), EtOAc (100ml) and 6.5%HCl (g) solution to (E)-1-(5-(3, the 4-dichlorophenyl) furans-2-yl) third-1-alkene-2-amine.Mixture is depressed (3.3 crust, Parr hydrogenation apparatus) hydrogenation 7 hours adding.Through diatomite filtration, evaporation is also passed through chromatogram purification (CombiFlash, silicagel column, eluent: 5-20%MeOH/DCM) obtain 0.811g (29%) title compound, be HCl salt with reaction mixture. 1H-NMR(400MHz；d6-DMSO)：δ1.21(d，3H)，2.90(dd，1H)，3.04(dd，1H)，3.55(q，1H)，6.44(d，1H)，7.09(d，1H)，7.68(m，2H)，7.93(m，1H)。
C) the 3-tertiary butyl-N-(1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
With the 5-tertiary butyl-2H-pyrazoles-3-formic acid (94mg; 0.55mmol) be dissolved in DCM: DMF (4: 1,5ml).Add DCC (172mg; 0.83mmol).With 1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-amine (149mg; 0.55mmol) (77 μ l 0.55mmol) and with the solution that forms join in the reaction mixture to be dissolved in 2ml DCM and TEA.With reaction mixture stirred overnight at room temperature.Add DCM (50ml) then and with organic phase with water washing (2x30ml).Organic phase is used Na 2SO 4Drying, evaporation is also passed through chromatogram purification (CombiFlash, first silicagel column, eluent: 7.5-100%EtOAc/ heptane; Second silicagel column, eluent: 0-5%MeOH/DCM) obtain 35mg (15%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.19(d，3H)，1.27(s，9H)，2.88(dd，1H)，2.98(dd，1H)，4.33(quintet，1H)，6.29(d，1H)，6.33(s，1H)，7.00(d，1H)，7.60(m，2H)，7.83(d，1H)，7.89(d，1H)，12.84(s，1H)。
Embodiment 20
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
To the 5-pyridin-4-yl that is stirring-4H-pyrazoles-3-formic acid (1.78g, add in DCM 9.42mmol) (10ml) solution DIPEA (2.46ml, 14.1mmol), EDCI (2.71g, 9.42mmol) and HOBt (1.91,14.1mmol).With 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethylamine hydrochloride (2.75g, 9.42mmol) be dissolved in DCM (15ml) and DIPEA (1.64ml, 9.42mmol).The solution that forms is joined in the reaction mixture, with its stirred overnight at room temperature.With reaction mixture with DCM dilution and use saturated NaHCO 3The aqueous solution and water washing.Organic phase is used Na 2SO 4Drying, evaporation is also passed through chromatogram purification (CombiFlash, silicagel column, eluent 0-15%MeOH/DCM).Collection contains the level of product and divides, evaporation and with the DCM crystallization and with 2%MeOH/DCM and heptane recrystallization.Obtain 1.18g (29%) title compound thus. 1H-NMR(400MHz；d6-DMSO)：δ2.97(t，2H)，3.59(q，2H)，6.35(d，1H)，7.03(d，1H)，7.33(s，1H)，7.62(d，2H)，7.75(m，2H)，7.84(t，1H)，8.57(br?s，1H)，8.63(m，2H)，13.95(s，1H)。
Embodiment 21
The 3-tertiary butyl-N-(2-(5-(3,4-dicyano phenyl) furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide
{ [5-(3 for 2-to the 5-of the embodiment that is stirring 18 tertiary butyl-2H-pyrazoles-3-formic acid; 4-two chloro-phenyl)-furans-2-yl]-ethyl }-acid amides (128mg; 0.315mmol) DMF/ water (99: 1; 1ml) add in the solution zinc cyanide (81mg, 0.693mmol), S-Phos (26mg, 0.063mmol) and Pd 2(dba) 3(23mg, 0.025mmol).Reaction mixture was heated 40 minutes down at 150 ℃ through microwave reactor.Add 1.0M NaOH (20ml) and mixture is extracted (3x20ml) with EtOAc.The organic phase that merges is used Na 2SO 4Drying, evaporation is also passed through chromatogram purification (CombiFlash, first silicagel column: eluent 0-100%EtOAc/ heptane; Second post C-18RP: eluent 0-100%MeCN/ water) obtain 25mg (20%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.27(s，9H)，2.96(t，2H)，3.57(q，2H)，6.35(br?s，1H)，6.44(d，1H)，7.31(d，1H)，8.07(dd，1H)，8.11(d，1H)，8.19(br?s，1H)，8.38(d，1H)，12.87(br?s，1H)。
Embodiment 22
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-methyl isophthalic acid H-pyrazoles-5-methane amide
This title compound utilizes the method for embodiment 20 to prepare as raw material with 3-methyl isophthalic acid H-pyrazoles-5-formic acid and 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethylamine hydrochloride.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: the 0-100%EtOAc/ heptane) obtain 301mg (28%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.25(s，3H)，2.92(t，2H)，3.53(q，2H)，6.32(d，1H)，6.34(s，1H)，7.01(d，1H)，7.63(m，2H)，7.85(s，1H)，8.16(t，1H)，13.86(s，1H)。
Embodiment 23
N-(2-(5-(3,4-dicyano phenyl) furans-2-yl) ethyl)-3-methyl isophthalic acid H-pyrazoles-5-methane amide
This title compound is according to the method for embodiment 21, but prepares as raw material with N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-methyl isophthalic acid H-pyrazoles-5-methane amide.Crude product is passed through chromatogram purification (CombiFlash, first silicagel column, eluent: 0-10%MeOH/DCM; Second post C-18RP, eluent: 0-100%MeCN/ water) to obtain 45mg (16%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.24(s，3H)，2.96(t，2H)，3.55(q，2H)，6.35(s，1H)，6.43(d，1H)，7.31(d，1H)，8.07(dd，1H)，8.12(d，1H)，8.20(br?s，1H)，8.34(d，1H)，12.87(s，1H)。
Embodiment 24
(S/R)-N-(1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-yl)-3-methyl isophthalic acid H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 19 with the form of racemic modification but prepares as raw material with 3-methyl isophthalic acid H-pyrazoles-5-formic acid and 1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-amine hydrochlorate.Obtain 79mg (32%) title compound thus.Enantiomorph is obtained other enantiomorph of 16mg (optical purity 98.8%) (=compound 24A) and the other enantiomorph (optical purity 98.3%) (=compound 24B) of 16mg through chromatographic separation (SFCMinigram, Mettler Toledo).The absolute configuration of the enantiomorph that goes out of analytical separation not.
Compound 24A: 1H-NMR (400MHz; CDCl 3): δ 1.26 (d, 3H), 2.34 (s, 3H), 2.91 (dd, 1H), 3.01 (dd, 1H), 4.52 (m, 1H), 6.20 (d, 1H), 6.56 (s, 1H), 6.57 (d, 1H), 7.12 (d, 1H), 7.38 (d, 1H), 7.41. (dd, 1H), 7.78 (d, 1H), 10.26 (s, 1H).
Compound 24B: 1H-NMR (400MHz; CDCl 3): δ 1.26 (d, 3H), 2.34 (s, 3H), 2.91 (dd, 1H), 3.01 (dd, 1H), 4.52 (m, 1H), 6.20 (d, 1H), 6.56 (s, 1H), 6.57 (d, 1H), 7.12 (d, 1H), 7.38 (d, 1H), 7.41. (dd, 1H), 7.78 (d, 1H), 10.31 (s, 1H).
Embodiment 25
(S/R)-N-(1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-yl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 19 with the form of racemic modification but prepares as raw material with 5-pyridin-4-yl-4H-pyrazoles-3-formic acid and 1-(5-(3, the 4-dichlorophenyl) furans-2-yl) propane-2-amine hydrochlorate.Obtain 90mg (31%) title compound thus.Enantiomorph is obtained other enantiomorph of 16mg (optical purity 100%) (=compound 25A) and the other enantiomorph (optical purity 100%) (=compound 25B) of 11mg through chromatographic separation (SFC Minigram, Mettler Toledo).The absolute configuration of the enantiomorph that goes out of analytical separation not.
Compound 25A: 1H-NMR (400MHz; D6-DMSO): δ 1.24 (d, 3H), 2.95 (m, 2H), 4.35 (m, 1H), 6.31 (d, 1H), 7.00 (d, 1H), 7.35 (s, 1H), 7.58 (s, 2H), 7.73 (m, 2H), 7.93 (s, 1H), 8.33 (br s, 1H), 8.63 (d, 2H), 13.88 (s, 1H).Compound 25B: 1H-NMR (400MHz; D6-DMSO): δ 1.24 (d, 3H), 2.95 (m, 2H), 4.35 (m, 1H), 6.31 (d, 1H), 7.00 (d, 1H), 7.35 (s, 1H), 7.58 (s, 2H), 7.73 (m, 2H), 7.79 (s, 1H), 8,33 (br s, 1H), 8.63 (d, 2H), 13.88 (s, 1H).
Embodiment 26
1-(pyridine-2-yl)-1H-imidazoles-4-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides
Title compound is synthetic through .Tetrahedron Lett.48 (2007) 4207 described methods such as A.K.Verma from 1H-imidazoles-4-formic acid { 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] ethyl } acid amides and the 2-bromopyridine of embodiment 15.Through purification by flash chromatography, utilize CH 2Cl 2/ MeOH is as gradient elution agent (100: 0-99.9: 0.1) obtain product, it is at room temperature developed with EtOAc obtain required product. 1H NMR (400MHz, DMSO-d 6): 2.96 (2H, t), 3.59 (2H, m), 6.35 (1H, d), 7.03 (1H, d), 7.44 (1H, m), 7.63 (2H, s), 7.84 (1H, s), 7.95 (1H, distored d), 8.05 (1H, m), 8.33 (1H, t), 8.43 (1H, d), 8.54 (1H, m), 8.64 (1H, d, 4J=1.1Hz).
Embodiment 27
N-(2-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) ethyl)-3-methyl isophthalic acid H-pyrazoles-5-methane amide is 2-(2-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) ethyl) xylylenimine-1 a), the 3-diketone
(96mg adds 3-(3, the 4-dichlorophenyl)-1H-pyrazoles (0.426g, DMF 2.0mmol) (2.0ml) solution in DMF 2.4mmol) (1.0ml) suspension-s to the sodium hydride that cools off (0 ℃).Reaction mixture was at room temperature stirred 45 minutes.In the reaction mixture of cooling (0 ℃), add N-(2-bromotrifluoromethane) phthalic imidine (0.610g, DMF 2.4mmol) (1.0ml) solution.With reaction mixture stirred overnight at room temperature.Add entry (100ml) and mixture is extracted (3x50ml) with DCM.The organic phase that merges is used Na 2SO 4Dry also through chromatogram purification (CombiFlash, C-18RP post, eluent: 0-100%MeCN/ water) obtain 0.155g (20%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ3.98(t，2H)，4.26(t，2H)，6.74(d，1H)，7.45(dd，1H)，7.50(d，1H)，7.55(d，1H)，7.82(m，5H)。
B) 2-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) ethamine
To the 2-that is stirring (2-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) ethyl) xylylenimine-1, the 3-diketone (155mg, add in EtOH 0.40mmol) (4.0ml) solution Hydrazine Hydrate 80 (0.194ml, 4.0mmol).With reaction mixture refluxed 1 hour and be cooled to room temperature.Add entry (20ml) and mixture is extracted (3x20ml) with DCM.The organic phase that merges is used Na 2SO 4Dry and evaporation obtains the title compound (102mg, 100%) of quantitative yield.Product promptly is used for next step without analyzing.
C) N-(2-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) ethyl)-3-methyl isophthalic acid H-pyrazoles-5-methane amide
To the 3-methyl isophthalic acid H-pyrazoles-5-formic acid that is stirring (104mg, add in DCM 0.83mmol) (2.0ml) solution DIPEA (0.144ml, 0.83mmol), EDCI (159mg, 0.83mmol) and HOBt (112mg, 0.83mmol).(102mg 0.40mmol) joins in DCM (2.0ml) solution of reaction mixture with 2-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) ethamine after 10 minutes.With reaction mixture stirred overnight at room temperature.With reaction mixture with DCM dilution and use saturated NaHCO 3The aqueous solution and water washing.Organic phase is used Na 2SO 4Drying, evaporation is also passed through chromatogram purification (CombiFlash, first silicagel column, eluent: 0-10%MeOH/DCM; Second post C-18RP, eluent: 0-100%MeCN/ water) obtain 65mg (45%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.24(s，3H)，3.64(q，2H)，4.31(t，2H)，6.36(s，1H)，6.81(d，1H)，7.65(d，1H)，7.77(d，1H)，7.80(dd，1H)，8.00(d，1H)，8.23(s，1H)，12.88(s，1H)。
Embodiment 28
N-(2-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
A) 2-methyl-4-(1H-pyrazole-3-yl) benzonitrile
Title compound utilizes the method for embodiment 34 (b) but synthesizes as raw material with 4-bromo-2-methyl benzonitrile and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl)-1H-pyrazoles. 1H-NMR(400MHz；CDCl 3)：δ2.60(s，3H)，6.69(d，1H)，7.64(m，2H)，7.70(d，1H)，7.78(s，1H)，10.47(br?s，1H)。
B) 4-(1-(2-(1,3-dioxo xylylenimine-2-yl) ethyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile
(0.949g, 5.2mmol) (1.58g 6.2mmol) utilizes the method for embodiment 27 (a) to react with N-(2-bromotrifluoromethane) phthalic imidine with 2-methyl-4-(1H-pyrazole-3-yl) benzonitrile.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: the 0-100%EtOAc/ heptane) obtain 0.590g (32%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.36(s，3H)，3.99(t，2H)，4.44(t，2H)，6.76(d，1H)，7.44(s，1H)，7.46(m，1H)，7.62(d，1H)，7.83(m，5H)。
C) 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile
(0.590g 1.66mmol) utilizes the method for embodiment 27 (b) to handle with Hydrazine Hydrate 80 with 4-(1-(2-(1,3-dioxo xylylenimine-2-yl) ethyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile.Obtain 362mg (96%) title compound thus. 1H-NMR(400MHz；d6-DMSO)：δ2.52(s，3H)，2.95(t，2H)，4.13(t，2H)，6.84(d，1H)，7.77(m，2H)，7.82(d，1H)，7.89(m，1H)。
D) N-(2-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
Title compound from 5-pyridin-4-yl-4H-pyrazoles-3-formic acid (303mg, 1.60mmol) and 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile (362mg 1.60mmol) utilizes the method preparation of embodiment 34 (d).Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-20%MeOH/DCM) obtain 44mg (6%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.49(s，3H)，3.71(q，2H)，4.37(t，2H)，6.84(d，1H)，7.31(s，1H)，7.74(m，2H)，7.70(s，1H)，7.79(dd，1H)，7.83(d，1H)，7.88(s，1H)，8.55(br?s，1H)，8.63(m，2H)，13.99(s，1H)。
Embodiment 29
(S)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
A) (S)-4-(1-(2-(1,3-dioxo xylylenimine-2-yl) propyl group)-1H-pyrazole-3-yl)-2-methyl benzonitrile
With 2-methyl-4-(1H-pyrazole-3-yl) benzonitrile (2.35g, 12.2mmol) with (S)-2-(1-N-PROPYLE BROMIDE-2-yl) xylylenimine-1, (3.61g 13.5mmol) utilizes the method for embodiment 27 (a) to react to the 3-diketone.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: the 0-100%EtOAc/ heptane) obtain 1.15g (25%) title compound. 1H-NMR(400MHz；CDCl 3)：δ1.59(d，3H)，2.47(s，3H)，4.41(m，1H)，4.83(m，2H)，6.46(d，1H)，7.39(m，2H)，7.47(m，2H)，7.69(m，2H)，7.78(m，2H)。
B) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile
(481mg 1.3mmol) utilizes the method for embodiment 27 (b) to handle with Hydrazine Hydrate 80 with (S)-4-(1-(2-(1,3-dioxo xylylenimine-2-yl) propyl group)-1H-pyrazole-3-yl)-2-methyl benzonitrile.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-20%MeOH/DCM) obtain 59mg (19%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ0.96(d，3H)，2.52(s，3H)，3.23(m，1H)，4.00(m，2H)，6.85(d，1H)，7.77(m，2H)，7.81(d，1H)，7.89(m，1H)。
C) (S)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
Title compound from 5-pyridin-4-yl-4H-pyrazoles-3-formic acid (47mg, 0.25mmol) with (S)-(59mg 0.25mmol) utilizes the method preparation of embodiment 34 (d) to 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-20%MeOH/DCM) obtain 41mg (40%) title compound. 1H-NMR(400MHz；MeOD)：δ1.24(d，3H)，2.52(s，3H)，4.32(m，2H)，4.53(m，1H)，6.59(d，1H)，7.15(m，1H)，7.36(s，2H)，7.53(d，1H)，7.58(m，2H)，7.70(m，2H)，8.53(br?s，1H)，8.56(d，1H)。
Embodiment 30
(R)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
A) (R)-2-(1-hydroxy propane-2-yl) xylylenimine-1, the 3-diketone
With the D-aminopropanol (3.90ml, 50mmol) and Tetra hydro Phthalic anhydride (7.41g is 50mmol) 160 ℃ of down heating 30 minutes.In the refrigerative reaction mixture, add frozen water and DCM.Organic phase is collected and water is extracted with DCM.The organic phase that merges is used Na 2SO 4Dry and evaporation obtains 8.75g (85%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.32(d，3H)，3.54(m，1H)，3.84(m，1H)，4.26(m，1H)，4.91(m，1H)，7.84(m，4H)。
B) (R)-and 2-(1-N-PROPYLE BROMIDE-2-yl) xylylenimine-1, the 3-diketone
With (R)-2-(1-hydroxy propane-2-yl) xylylenimine-1, the 3-diketone (8.75g, 43mmol) and phosphorus tribromide (2.73ml is 29mmol) 175 ℃ of down heating 50 minutes.In the refrigerative reaction mixture, add ice (50ml).Formed throw out is filtered, obtain 11.1g (97%) title compound with water washing and vacuum-drying. 1H-NMR(400MHz；d6-DMSO)：δ1.50(d，3H)，3.85(m，1H)，4.01(m，1H)，4.49(m，1H)，7.88(m，4H)。
C) (R)-4-(1-(2-(1,3-dioxo xylylenimine-2-yl) propyl group)-1H-pyrazole-3-yl)-2-methyl benzonitrile
With 2-methyl-4-(1H-pyrazole-3-yl) benzonitrile (2.23g, 12.2mmol) with (R)-2-(1-N-PROPYLE BROMIDE-2-yl) xylylenimine-1, (3.92g 14.6mmol) utilizes the method for embodiment 27 (a) to react to the 3-diketone.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: the 0-100%EtOAc/ heptane) obtain 0.753g (17%) title compound.Product promptly is used for next step without analyzing.
D) (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile
(753mg 2.0mmol) utilizes the method for embodiment 27 (b) to handle with Hydrazine Hydrate 80 with (R)-4-(1-(2-(1,3-dioxo xylylenimine-2-yl) propyl group)-1H-pyrazole-3-yl)-2-methyl benzonitrile.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-20%MeOH/DCM) obtain 82mg (17%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ0.96(d，3H)，2.52(s，3H)，3.22(m，1H)，3.99(m，2H)，6.84(d，1H)，7.77(m，2H)，7.81(d，1H)，7.89(m，1H)。
E) (R)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-4-yl)-1H-pyrazoles-5-methane amide
Title compound from 5-pyridin-4-yl-4H-pyrazoles-3-formic acid (13mg, 0.069mmol) with (R)-(17mg 0.071mmol) utilizes the method preparation of embodiment 34 (d) to 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-20%MeOH/DCM) obtain 19mg (67%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.17(d，3H)，2.48(s，3H)，4.31(m，2H)，4.47(m，1H)，6.82(d，1H)，7.31(s，1H)，7.75(m，4H)，7.81(d，1H)，7.85(s，1H)，8.40(d，1H)，8.63(m，2H)，13.92(br?s，1H)。
Embodiment 31
N-(2-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) ethyl)-3-methyl isophthalic acid H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 28 (d) to prepare as raw material with 3-methyl isophthalic acid H-pyrazoles-5-formic acid.Crude product is passed through chromatogram purification (CombiFlash, first silicagel column, eluent: 0-15%MeOH/DCM; Second post C-18RP, eluent: 0-100%MeCN/ water) obtain 39mg (42%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.24(s，3H)，2.52(s，3H)，3.65(q，2H)，4.33(t，2H)，6.36(s，1H)，6.83(d，1H)，7.79(m，3H)，7.88(s，1H)，8.24(br?s，1H)，12.85(br?s，1H)。
Embodiment 32
(S)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 29 but replaces 5-pyridin-4-yl-4H-pyrazoles-3-formic acid to synthesize with 5-(2-furyl)-4H-pyrazoles-3-formic acid.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: the 0-100%EtOAc/ heptane) obtain 39mg (75%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.14(d，3H)，2.49(s，3H)，4.30(m，2H)，4.45(m，1H)，6.61(m，1H)，6.80(s，1H)，6.82(d，1H)，6.91(s，1H)，7.76(m，3H)，7.80(d，1H)，7.85(s，1H)，8.36(d，1H)，13.69(s，1H)。
Embodiment 33
(R)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(morpholine-4-carbonyl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 30 but with 3,5-pyrazoles dioctyl phthalate replaces 5-pyridin-4-yl-4H-pyrazoles-3-formic acid to synthesize.5-(piperazine-1-carbonyl)-{ [5-(3 for 2-for 2H-pyrazoles-3-formic acid according to synthesizing among the embodiment 1 with morpholine with resulting (R)-5-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-pyrazoles-3-formic acid; The 4-dichlorophenyl) furans-2-yl] ethyl } the method coupling of acid amides, but with morpholino TEPA piperazine.Crude product is passed through chromatogram purification (CombiFlash, first silicagel column, eluent: 0-10%MeOH/DCM; Second post C-18RP, eluent: 0-100%MeCN/ water) obtain 24mg (45%) title compound. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，2.60(s，3H)，3.79(m，8H)，4.29(dd，1H)，4.42(dd，1H)，4.60(m，1H)，6.61(d，1H)，7.02(s，1H)，7.47(d，1H)，7.63(m，2H)，7.72(d，1H)，7.79(s，1H)，11.09(s，1H)。
Embodiment 34
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 2-chloro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
With 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl)-1H-pyrazoles (6.5g; 23.28mmol) and 4-bromo-2-benzyl chloride nitrile (4g; 18.48mmol) be dissolved in THF (65ml).In this mixture, add two (triphenylphosphine) Palladous chloride (II) (0.65g; 0.92mmol), yellow soda ash (4.7g; 44.3mmol) and 18ml water and reaction mixture stirred 2.5 hours down at 35 ℃.Solvent distillation is to almost dry and add entry (48ml).Stir after 30 minutes, the product that deposition is separated out filters and 32ml ethanol is joined in the throw out.Suspension-s was at room temperature stirred 15 minutes, stirred 30 minutes down, filter then and obtain the 3.7g product at-10 ℃. 1H-NMR(400MHz；d6-DMSO)：δ1.63-1.54(m，3H)，1.84-1.80(m，1H)，1.97-1.94(m，1H)，2.39-2.35(m，1H)，3.63-3.57(m，1H)，3.99(m，1H)，5.32-5.27(m，1H)，6.72(d，1H)，7.65(d，1H)，7.72(m，1H)，7.92(d，1H)，8.14(d，1H)。
B) 2-chloro-4-(1H-pyrazoles-5-yl) benzonitrile
With 2-chloro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile (3.67g; 12.75mmol) under nitrogen, join in the 8ml ethanol.Slowly add the EtOH solution of 15.5ml～10%HCl (g) and temperature is risen to 30 ℃, mixture was stirred 1 hour.Cool the temperature to-10 ℃ and mixture stirred 30 minutes once more then, this moment, product was separated out with the form deposition of its HCl salt, filtered, with twice of 2ml washing with alcohol.With product+40 ℃ of following vacuum-dryings.Yield 2.8g.With 2-chloro-4-(1H-pyrazoles-5-yl) benzonitrile hydrochloride (2.8g; 11.47mmol) under nitrogen, join in the mixture of 8ml water and 14ml MeOH.To wherein adding 50% sodium hydroxide (1.5ml; 28.7mmol), in adition process, temperature is remained on below 25 ℃.Mixture was stirred 2 hours, throw out is filtered and with twice of the water washing of 3ml tepor.With product+40 ℃ of following vacuum-dryings.Yield 1.97g. 1H-NMR(400MHz；d6-DMSO)：δ6.99(t，1H)，7.89(m，1H)，7.99(d，2H)，8.15(s，1H)，13.27(s，1H)。
C) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
With 2-chloro-4-(1H-pyrazole-3-yl) benzonitrile (4.00g; 19.64mmol), (S)-tertiary butyl-1-hydroxy propane-2-aminocarbamic acid ester (3,79g; 21.61mmol) and triphenylphosphine under nitrogen, be dissolved in exsiccant THF and stir.Drip diisopropyl azodiformate (7.74ml; 39.3mmol) and reaction flask is passed through ice bath cool off.With reaction solution stirred overnight (18h) and be evaporated to dried at room temperature.For the Boc deprotection, 200ml10%HCl/EtOH solution is joined in the vaporized residue, at room temperature stirred 20 hours and be evaporated to dried.With 100ml water join in the vaporized residue and with the 3x120mlDCM washing to remove remaining reactant.The pH of water is adjusted to through adding 2M NaOH～12, use Na with 3x 80ml DCM washing and with organic phase 2SO 4Dry.Organic phase filtration and evaporation are obtained the 2.605g title compound.
D) (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
With 3-ethanoyl-1H-pyrazoles-5-formic acid (0.59g; 3.84mmol) and DIPEA (1.0ml; 5.75mmol) be dissolved in 4ml exsiccant DCM.At room temperature add anhydrous HOBt (0.78g; 5.75mmol) and EDCI (1.10g; 5.75mmol).With (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (1.00g; 3.84mmol) be dissolved in 4ml DCM and with reaction solution stirred overnight at room temperature.Add 40ml DCM and with organic layer with 3x 15ml water washing.The water that merges is washed with 2x 20mlDCM.Two parts of organic phases are used Na 2SO 4Drying filters and is evaporated to dried.Two crude product levels are divided merging and passed through CombiFlash purifying (the DCM solution of 2%MeOH).Divide merging and evaporation to obtain the 497mg product product level. 1H-NMR(400MHz；d6-DMSO)：δ1.16(d，3H，J＝6.7Hz)，2.49(s，3H)，4.31(m，2H)，4.46(sept，1H，J＝6.7Hz)，6.93(d，1H，J＝2.4Hz)，7.31(s，1H)，7.81(d，1H，J＝2.4Hz)，7.92(d，1H，J＝7.9Hz)，7.97(d，1H，J＝8.1Hz)，8.03(d，1H，J＝1.3Hz)，8.48(d，1H，J＝8.5Hz)，14.16(s，1H)。
Embodiment 35
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-(morpholine-4-carbonyl) pyrazine-2-methane amide
A) 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
Title compound utilizes the method for embodiment 34 (c) with 2.3g 2-chloro-4-(1H-pyrazoles-5-yl) benzonitrile hydrochloride, and 1.7ml DIPEA and 1.7g 2-hydroxyethyl t-butyl carbamate prepare as raw material, obtain the 2.08g product. 1H-NMR(400MHz；d 6-DMSO)：δ1.56(s，2H)，2.97(t，2H)，4.13-4.17(t，2H)，6.97(s，1H)，7.87(d，1H)，7.93-8.02(m，2H)，8.10(d，1H)。
B) 5-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethylamino formyl radical) pyrazine-2-formic acid
With pyrazine-2,5-dioctyl phthalate (0.53g; 3.18mmol), anhydrous HOBt (0.43g; 3.18mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.61g; 3.18mmol) and DIPEA (0.55ml; 3.18mmol) be dissolved in 5ml exsiccant DCM.With 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.6g; 2.12mmol) and DIPEA (0.55ml; 3.18mmol) be dissolved in 5ml exsiccant DCM and be added drop-wise in the aforementioned mixture.With the reaction mixture stirred overnight, add pyrazine-2 then, 5-dioctyl phthalate (0.27g; 1.59mmol), anhydrous HOBt (0.52g; 3.81mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.41g: 2.12mmol) and DIPEA (0.37ml; 2.12mmol) accomplish to drive reaction.2.5 after hour mixture is diluted with 20ml DCM.After adding 10ml water, the product deposition is separated out, and filters and obtains the 0.42g crude product, and it can use without being further purified.
C) N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-(morpholine-4-carbonyl) pyrazine-2-methane amide
With 5-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethylamino formyl radical) pyrazine-2-formic acid (0.11g; 0.29mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.083g: 0.43mmol), anhydrous HOBt (0.058g; 0.43mmol), DIPEA (0.075ml; 0.43mmol) and morpholine (0.025g; 0.29mmol) be dissolved in 5ml exsiccant DCM and stirred overnight.With solution with 10ml DCM dilution and with 3x 5ml water washing.The water that merges is used Na with 2x5ml DCM extraction and with the organic phase that merges 2SO 4Drying filters and is evaporated to dried.Product is used purification by flash chromatography, with DCM/MeOH as the gradient elution agent.Yield 0.06g. 1H-NMR(400MHz；d 6-DMSO)：δ3.45(t，2H)，3.56(t，2H)，3.69(s，4H)，3.76-3.80(m，2H)，4.42(t，2H)，6.97(d，1H)，7.87(d，1H)，7.94-8.01(m，2H)，8.01(s，1H)，8.93(d，1H)，9.13(s，1H)，9.22-9.25(t，1H)。
Embodiment 36
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-oxo-1-phenyl-2,5-dihydro-1 h-pyrazole-3-methane amide
A) 5-oxo-1-phenyl-2,5-dihydro-1 h-pyrazole-3-methyl-formiate
With phenyl hydrazine (0.5g; 4.62mmol), acetylene dioctyl phthalate dimethyl ester (0.66g; 4.62mmol) and 4-toluenesulphonic acids pyridinium salt (1.16g; 4.62mmol) under nitrogen, be dissolved in 7ml exsiccant THF and solution at room temperature stirred 2 hours, add the EtOAc solution of 7ml10%HCl (g) then and with mixture 67 ℃ of heating 5 hours down.Reaction mixture is evaporated to dry doubling to join 6ml DCM in the resistates.Organic phase is extracted with 2x 6ml DCM with the 8ml water washing and with the water that merges.The organic phase that merges is used the 12ml water washing once once more, use Na 2SO 4The dried 0.35g of obtaining product is filtered and be evaporated to drying, and it can use without being further purified.
B) 5-oxo-1-phenyl-2,5-dihydro-1 h-pyrazole-3-formic acid
With 5-oxo-1-phenyl-2,5-dihydro-1 h-pyrazole-3-methyl-formiate (0.35g; 1.60mmol) 5ml 2M NaOH solution 60 ℃ of down heating 2 hours, then with reaction mixture with the dense HCl acidifying of 1.5ml, it causes product formation yellow mercury oxide.Filtration obtains the 0.18g product. 1H-NMR(400MHz；d 6-DMSO)：δ5.97(s，1H)，7.33-7.37(m，1H)，7.48-7.52(m，2H)，7.74(m，2H)。
C) N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-oxo-1-phenyl-2,5-dihydro-1 h-pyrazole-3-methane amide
With 5-oxo-1-phenyl-2,5-dihydro-1 h-pyrazole-3-formic acid (0.05g; 0.24mmol), HOBt (0.049g; 0.37mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.07g; 0.37mmol) join among the 2.5ml DCM.To wherein dripping 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.06g; 0.24mmol) and DIPEA (0.064ml; 0.37mmol) and with the mixture stirred overnight, add 10ml DCM then.Mixture is extracted with 2x 5ml DCM with 3x 5ml water washing and with the water that merges.The organic layer that merges is used Na 2SO 4Drying filters and is evaporated to dried.Product is used purification by flash chromatography, utilize DCM/MeOH as the gradient elution agent.Level branch by merging obtains the 18mg product. 1H-NMR(400MHz；d 6-DMSO)：δ1.23(s，1H)，3.65-3.70(m，2H)，4.37(t，2H)，5.83(s，1H)，6.97(d，1H)，7.31-7.35(t，1H)，7.45-7.49(t，2H)，7.76(d，2H)，7.85-7.89(m，2H)，7.94-7.96(m，1H)，8.09(d，1H)，8.28(m，1H)。
Embodiment 37
3-methyl-N-(2-(3-(8-nitroisoquinoline-5-yl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazoles-5-methane amide
A) 8-nitro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) isoquinoline 99.9
Title compound utilizes the method for embodiment 34 (a) to prepare as raw material with 0.5g 5-bromo-8-nitroisoquinoline.Yield 0.49g. 1H-NMR(400MHz；d 6-DMSO)：δ1.43-1.51(m，3H)，1.80-1.89(m，2H)，2.32-2.33(m，1H)，3.25-3.27(m，1H)，3.76-3.78(m，1H)，5.06(d，1H)，6.65(d，1H)，6.68(d，1H)，7.78(d，1H)，8.02(d，1H)，8.54(d，1H)，8.72(d，1H)，9.84(s，1H)。
B) 8-nitro-5-(1H-pyrazoles-5-yl) isoquinoline 99.9
Title compound utilizes the method preparation of embodiment 34 (b) from 8-nitro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) isoquinoline 99.9 (0.49g).Yield 0.35g. 1H-NMR(400MHz；d 6-DMSO)：δ6.92(d，1H)，8.00(br?s，1H)，8.18(d，1H)，8.48(d，1H)，8.75(d，1H)，8.87(br?s，1H)，9.84(s，1H)，13.50(br?s，1H)。
C) 2-(3-(isoquinoline 99.9-5-yl)-1H-pyrazol-1-yl) ethamine
In 0.50g 8-nitro-5-(1H-pyrazoles-5-yl) isoquinoline 99.9, add 5ml exsiccant DMF and mixture was at room temperature stirred 30 minutes.To wherein add with 1.5ml exsiccant DMF dilution 0.65g 2-(tert-butoxycarbonyl amino) ethyl methane sulfonate ester and with mixture 160 ℃ of following microwave heatings 30 minutes.Mixture is poured in the water, extracted with EtOAc then.With the organic phase water and the brine wash that merge, use Na 2SO 4Dry also evaporation.Crude product is passed through CombiFlash purifying (the DCM solution of 5%MeOH).Divide merging and evaporation to obtain the product of 0.59g Boc-protection the product level.For the Boc deprotection, 8ml10%HCl/EtOH solution is joined in the vaporized residue, at room temperature be stirred to through TLC and confirm that raw material disappears.The 3ml diethyl ether is joined in the mixture and throw out is filtered, obtain the 0.30g product, be HCl-salt with diethyl ether washing and drying. 1H-NMR(400MHz；d 6-DMSO)：δ1.57(br?s，2H)，3.04(t，2H)，4.25(t，2H)，6.90(d，1H)，8.00(d，1H)，8.17(d，1H)，8.47(d，1H)，8.75(d，1H)，8.91(d，1H)，9.83(s，1H)。
D) 3-methyl-N-(2-(3-(8-nitroisoquinoline-5-yl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazoles-5-methane amide.
Title compound utilizes the method preparation of embodiment 34 (d) from 2-(3-(isoquinoline 99.9-5-yl)-1H-pyrazol-1-yl) ethamine (0.15g) and 3-methyl isophthalic acid H-pyrazoles-5-formic acid (0.080g).Yield 0.15g. 1H-NMR(400MHz；d 6-DMSO)：δ2.25(s，3H)，3.75(t，2H)，4.56(t，2H)，6.35(s，1H)，6.88(d，1H)，7.96(d，1H)，8.16(d，1H)，8.21(br?s，1H)，8.47(d，1H)，8.62(d，1H)，8.88(d，1H)，9.82(s，1H)，12.90(br?s，1H)。
Embodiment 38
3-(furans-2-yl)-N-(2-(3-(2-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazoles-5-methane amide
A) 5-(2-methoxyl group-4-nitrophenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles
Title compound utilizes the method for embodiment 34 (a) to prepare as raw material with 2.46g 1-iodo-2-methoxyl group-4-oil of mirbane.Yield 1.88g. 1H-NMR(400MHz；d 6-DMSO)：δ1.41-1.63(m，3H)，1.80-1.87(m，1H)，1.90-1.98(m，1H)，2.26-2.38(m，1H)，3.35-3.42(m，1H)，3.80-3.85(m，1H)，3.92(s，3H)，5.05(d，1H)，6.44(d，1H)，7.60(d，1H)，7.61(d，1H)，7.91(d，1H)，7.95(d，1H)。
B) 5-(2-methoxyl group-4-nitrophenyl)-1H-pyrazoles
Title compound utilizes the method preparation of embodiment 34 (b) from 1.88g 5-(2-methoxyl group-4-nitrophenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles.Yield 1.32g. 1H-NMR(400MHz；d 6-DMSO)：δ4.02(s，3H)，6.90(d，1H)，7.82-7.86(m，3H)，8.21(d，1H)，13.2(br?s，1H)。
C) 2-(3-(2-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethamine
Title compound utilizes the method preparation of embodiment 37 (c) from 5-(2-methoxyl group-4-nitrophenyl)-1H-pyrazoles (1.00g) and 2-(tert-butoxycarbonyl is amino) ethyl methane sulfonate ester (1.42g).Yield 0.24g (being HCl-salt). 1H-NMR(400MHz；d 6-DMSO)：δ3.32(t，2H)，4.02(s，3H)，4.47(t，2H)，6.94(d，1H)，7.88-7.93(m，3H)，8.12(br?s，2H)，8.22(d，1H)。D) 3-(furans-2-yl)-N-(2-(3-(2-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 2-(3-(2-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethamine (0.11g) and 3-(furans-2-yl)-1H-pyrazoles-5-formic acid (0.079g).Yield 0.11g. 1H-NMR(400MHz；d 6-DMSO)：δ3.71(t，2H)，4.01(s，3H)，4.39(t，2H)，6.57-6.68(m，2H)，6.85-6.89(m，2H)，7.76-7.93(m，4H)，8.15-8.22(m，1H)，8.53(br?s，1H)，13.71(br?s，1H)。
Embodiment 39
N-(2-(3-(3-cyanic acid-4-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridine-2-yl)-1H-pyrazoles-5-methane amide
A) 2-nitro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
With 5-chloro-2-nitrobenzonitrile (1.5g), 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4; 4,5,5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-yl)-1H-pyrazoles (2.74g), PEPPSI ((1,3-two (2, the 6-diisopropyl phenyl) imidazoles-2-subunit) (3-chloropyridine base) palladium chloride (ii)) (0.11g), K 2CO 3DMF (2.27g) (30ml) and water (3ml) solution stirred 2.5 hours down at 90 ℃ under argon gas.Mixture poured in the water extract with EtOAc then.The organic phase that merges is used 5%NaHCO 3, water and brine wash, use Na 2SO 4Dry also evaporation.Resistates is developed with ethanol.Throw out is filtered and uses water washing.Yield 1.96g. 1H-NMR(400MHz；d 6-DMSO)：δ1.50-1.65(m，3H)，1.83-1.87(m，1H)，1.95-1.99(m，1H)，2.33-2.42(m，1H)，3.60-3.67(m，1H)，3.95-4.00(m，1H)，5.34(d，1H)，6.82(d，1H)，7.68(d，1H)，8.11(dd，1H)，8.32(d，1H)，8.54(d，1H)。
B) 2-nitro-5-(1H-pyrazoles-5-yl) benzonitrile
Title compound utilizes the method preparation of embodiment 34 (b) from 1.96g 2-nitro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile.Yield 1.40g. 1H-NMR(400MHz；d 6-DMSO)：δ7.10(d，1H)，7.90(d，1H)，8.37(dd，1H)，8.43(d，1H)，8.54(d，1H)，13.4(br?s，1H)。
C) 5-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile
Title compound utilizes the method preparation of embodiment 37 (c) from 2-nitro-5-(1H-pyrazoles-5-yl) benzonitrile (1.00g) and 2-(tert-butoxycarbonyl is amino) ethyl methane sulfonate ester (1.45g).Yield 0.32g (being HCl-salt). 1H-NMR(400MHz；d 6-DMSO)：δ3.34(t，2H)，4.50(t，2H)，7.15(d，1H)，7.99(d，1H)，8.21(br?s，2H)，8.39(dd，1H)，8.45(d，1H)，8.61(d，1H)。D) N-(2-(3-(3-cyanic acid-4-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridine-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 5-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile (0.10g) and 3-(pyridine-2-yl)-1H-pyrazoles-5-formic acid (0.077g).Yield 0.21g. 1H-NMR(400MHz；d 6-DMSO)：δ3.75(t，2H)，4.41(t，2H)，7.09(s，1H)，7.24-7.39(m，2H)，7.82-7.91(m，3H)，8.37-8.70(m，5H)，13.84(br?s，1H)。
Embodiment 40
N-(2-(3-(3,4-dicyano phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridine-2-yl)-1H-pyrazoles-5-methane amide
A) 4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) phthalonitrile
Title compound utilizes the method for embodiment 34 (a) to prepare as raw material with 2.29g 4-iodine phthalonitrile.Yield 2.28g. 1H-NMR(400MHz；d 6-DMSO)：δ1.50-1.65(m，3H)，1.82-1.86(m，1H)，1.94-1.99(m，1H)，2.32-2.41(m，1H)，3.58-3.64(m，1H)，3.94-3.97(m，1H)，5.33(d，1H)，6.76(d，1H)，7.67(d，1H)，8.06(dd，1H)，8.29(d，1H)，8.31(d，1H)。
B) 4-(1H-pyrazoles-5-yl) phthalonitrile
Title compound utilizes the method preparation of embodiment 34 (b) from 2.28g 4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) phthalonitrile.Yield 1.53g. 1H-NMR(400MHz；d 6-DMSO)：δ7.05(d，1H)，7.91(br?s，1H)，8.16(d，1H)，8.34(dd，1H)，8.54(d，1H)，13.36(br?s，1H)。
C) 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl) phthalonitrile
Title compound utilizes the method preparation of embodiment 37 (c) from 4-(1H-pyrazoles-5-yl) phthalonitrile (0.38g) and 2-(tert-butoxycarbonyl is amino) ethyl methane sulfonate ester (0.61g).Yield 0.050g (being HCl-salt). 1H-NMR(400MHz；d 4-MeOH)：δ3.50(t，2H)，4.54(t，2H)，6.94(d，1H)，7.81(d，1H)，7.98(d，1H)，8.28(dd，1H)，8.49(d，1H)。
D) N-(2-(3-(3,4-dicyano phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridine-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl) phthalonitrile (0.050g) and 3-(pyridine-2-yl)-1H-pyrazoles-5-formic acid (0.042g).Yield 0.062g. 1H-NMR(400MHz；d 6-DMSO)：δ3.72(t，2H)，4.40(t，2H)，7.01(s，1H)，7.27-7.40(m，2H)，7.88-7.94(m，3H)，8.14(d，1H)，8.32(d，1H)，8.35-8.65(m，3H)，13.9(br?s，1H)。
Embodiment 41
N-(2-(3-(3-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-5-methyl isophthalic acid H-pyrazole-3-formamide
A) 2-(3-(3-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethamine
With 5-(3-methoxyl group-4-nitrophenyl)-1H-pyrazoles (0.555g, 2.53mmol), 2-hydroxyethyl t-butyl carbamate (0.449g, 2.79mmol) and triphenylphosphine (0.863g 3.29mmol) mixes with THF (20ml) mutually.Adding DIAD (0.997ml, 5.06mmol).Mixture was stirred 3 hours.Add 10%EtOH/HCl (50ml).With the mixture stirred overnight.Desolvate through evaporating to remove.(20ml) joins in the resistates with water.This mixture is washed (2x 20ml) with DCM.Add 1M NaOH to reaching pH 14, then with DCM extraction (3x 20ml).Organic layer is merged, be evaporated to dried then.Carry out flash chromatography (gradient of DCM: MeOH) and obtain the 97mg title compound. 1H-NMR(400MHz；CDCl 3)：δ3.19-3.26(m，2H)，4.04(s，3H)，4.20-4.28(m，2H)，6.63(m，1H)，7.38-7.43(m，1H)，7.52(m.1H)，7.59(m，1H)，7.91-7.97(m，1H)。
B) N-(2-(3-(3-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-5-methyl isophthalic acid H-pyrazole-3-formamide
With 3-methylpyrazole-5-formic acid (70.0mg, 0.555mmol), (85mg's HOBt 0.629mmol) weighs in vial with PS-carbodiimide (672mg).Add DCM (4ml) and DMF (0.4ml).Mixture was stirred 10 minutes.(97mg 0.370mmol) and with mixture stirred 24 hours to add 2-(3-(3-methoxyl group-4-nitrophenyl)-1H-pyrazol-1-yl) ethamine.Leach solid.(616mg 1.849mmol) joins in the filtrating with the PS-triamine.Mixture was stirred 2 hours and filtered.To filtrate and concentrate and obtain the 46mg title compound through purification by flash chromatography (gradient of DCM: MeOH). 1H-NMR(400MHz；CDCl 3)：δ2.35(s，3H)，3.92，(m，2H)，4.05，(s，3H)，4.40，(t，2H)，6.57(s，1H)，6.61(d，1H)，7.31(s，1H)，7.40-7.43(m，1H)，7.47(d，1H)，7.62(d，1H)，7.96(d，1H)，9.94(s，1H)。
Embodiment 42
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000591
azoles-3-methane amide
With 5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000592
azoles-3-formic acid (57.9mg; 0.3mmol), (46mg 0.340mmol) mixes in vial with PS-carbodiimide (364mg), DCM (4ml) and DMF (0.4ml) HOBt mutually.With mixture vibration 10 minutes.(49mg 0.20mmol) and with mixture stirred 24 hours to add 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Leach solid.(333mg 1.0mmol) joins in the filtrating with the PS-triamine.With mixture vibration 4 hours and filtration.To filtrate and concentrate and obtain the 16mg title compound through purification by flash chromatography (gradient of DCM: MeOH). 1H-NMR(400MHz；d6-DMSO)：3.70δ(m，2H)，3.91(s，3H)，4.38(m，2H)，6.89(m，1H)，6.97(d，1H)，7.85(m，1H)，7.94-8.00(m，3H)，8.10(d，1H)，8.36(s，1H)，8.86-9.13(m，1H)。
Embodiment 43
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000593
azoles-3-methane amide
With 5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000594
azoles-3-formic acid (57.9mg; 0.3mmol), (46mg 0.340mmol) mixes in vial with PS-carbodiimide (364mg), DCM (4ml) and DMF (0.4ml) HOBt mutually.With mixture vibration 10 minutes.(51mg 0.2mmol) and with mixture stirred 24 hours to add (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Leach solid.(333mg 1.0mmol) joins in the filtrating with the PS-triamine.With mixture vibration 4 hours and filtration.To filtrate and concentrate and obtain the 12mg title compound through purification by flash chromatography (gradient of DCM: MeOH). 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，4.00(s，3H)，4.23-4.31(m，1H)，4.42-4.48(m，1H)，4.55-4.66(m，1H)，6.63(d，1H)，6.66(s，1H)，7.50(d，1H)，7.69(d，1H)，7.79-7.94(m，4H)，8.07(m，1H)。
Embodiment 44
(S)-N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000601
azoles-3-methane amide is 5-(1-methyl isophthalic acid H-pyrazoles-4-yl) different
Figure BDA0000157427790000602
azoles-3-formic acid (57.9mg; 0.3mmol), (46mg 0.340mmol) mixes in vial with PS-carbodiimide (364mg), DCM (4ml) and DMF (0.4ml) HOBt mutually.With mixture vibration 10 minutes.(48mg 0.2mmol) and with mixture stirred 24 hours to add (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile.Leach solid.(333mg 1.0mmol) joins in the filtrating with the PS-triamine.With mixture vibration 4 hours and filtration.To filtrate and concentrate and obtain the 15mg title compound through purification by flash chromatography (gradient of DCM: MeOH). 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，4.00(s，3H)，4.23-4.28(m，1H)，4.42-4.49(m，1H)，4.55-4.66(m，1H)，6.62(d，1H)，6.67(s，1H)，7.49(d，1H)，7.63(d，1H)，7.72-7.75(m，1H)，7.81(m，2H)，7.96(s，1H)，8.14(m，1H)。
Embodiment 45
N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-3-methylbutane-2-yl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
A) 4-(1-(2-amino-3-methylbutyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
Title compound utilizes the method for embodiment 34 (c) with 2-chloro-4-(1H-pyrazole-3-yl) benzonitrile (0.2g; 0.98mmol) and the 1-hydroxy-3-methyl butane-2-aminocarbamic acid tert-butyl ester (0.22g; 1.09mmol) prepare as raw material.Yield 22%. 1H-NMR(400MHz；CDCl 3)：δ1.02(m，6H)，1.71(m，1H)，3.14(m，1H)，3.95(m，1H)，4.27(m，1H)，6.61(d，1H)，7.51(d，1H)，7.66(d，1H)，7.77(dd，1H)，7.97(s，1H)。
B) N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-3-methylbutane-2-yl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with 4-(1-(2-amino-3-methylbutyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.060g; 0.21mmol) and 5-(pyridin-3-yl)-1H-pyrazoles-3-formic acid (0.039g; 0.21mmol) prepare as raw material.Crude product is utilized the cyanic acid column purification through flash chromatography, with the EtOAc/ heptane as eluent.Yield 12%. 1H-NMR(400MHz；MeOD)：δ1.14(m，6H)，1.95(m，1H)，4.35(m，2H)，4.55(m，1H)，6.71(s，1H)，7.02(m，1H)，7.53(m，1H)，7.72(m，3H)，7.95(s，1H)，8.25(m，1H)，8.54(m，1H)，8.88(m，1H)。
Embodiment 46
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl) pyrazolo [1,5-a] pyrimidine-2-methane amide
Title compound utilizes the method for embodiment 34 (d) with pyrazolo [1,5-a] pyrimidine-2-formic acid (0.16g; 0.97mmol) and 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.20g; 0.81mmol) prepare as raw material.Yield 12%. 1H-NMR(400MHz；d 6-DMSO)：δ3.75(q，2H)，4.41(t，2H)，6.96(d，1H)，7.03(s，1H)，7.19(m，1H)，7.86(d，1H)，7.97(m，2H)，8.06(s，1H)，8.64(m，1H)，8.71(m，1H)，9.09(d，1H)。
Embodiment 47
N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridine-2-yl)-1H-pyrazoles-5-methane amide
A) 2-nitro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
Title compound utilizes the method preparation of embodiment 39 (a) from 4-chloro-2-nitrobenzonitrile (1.50g) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl)-1H-pyrazoles (2.74g).Yield 1.75g. 1H-NMR(400MHz；d 6-DMSO)：δ1.57(m，3H)，1.84(m，1H)，1.97(m，1H)，2.38-2.47(m，1H)，3.68-3.75(m，1H)，4.03(m，1H)，5.33(dd，1H)，6.84(d，1H)，7.69(d，1H)，8.13(dd，1H)，8.31(d，1H)，8.60(d，1H)。
B) 2-nitro-4-(1H-pyrazoles-5-yl) benzonitrile
Title compound utilizes the method preparation of embodiment 34 (b) from 1.53g 2-nitro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile.Yield 1.0g. 1H-NMR(400MHz；d 6-DMSO)：δ7.09(d，1H)，7.92(s，1H)，8.19(d，1H)，8.37(dd，1H)，8.73(d，1H)，13.40(br?s，1H)。
C) 2-(tert-butoxycarbonyl is amino) ethyl methane sulfonate ester
N-(2-hydroxyethyl) t-butyl carbamate (6.0g), triethylamine (5.68ml) are dissolved in DM (50ml) and methylsulfonyl chloride (3.02ml) is added drop-wise in the reaction mixture under 0 ℃.Mixture was stirred 30 minutes and at room temperature continues stirring 2 hours down at 0 ℃.Add entry and mixture is extracted with DCM.With the organic phase water and the brine wash that merge, use Na 2SO 4Dry also evaporation.Product is stored under nitrogen.Yield 8.64g. 1H-NMR(400MHz；d 6-DMSO)：δ1.39(s，9H)，3.16(s，3H)，3.23(q，2H)，4.16(t，2H)，7.04(br?s，1H)。D) 2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) the ethyl carbamic acid tert-butyl ester
(60% oil solution 0.24g) at room temperature stirs 30 minutes with 2-nitro-4-(1H-pyrazoles-5-yl) benzonitrile (1.0g), DMF (10ml) and sodium hydride.Add DMF (3.3ml) solution of 2-(tert-butoxycarbonyl is amino) ethyl methane sulfonate ester (1.45g) and with mixture 160 ℃ of following microwave heatings 30 minutes (Biotage Initiator Sixty operates under 2.45GHz).Mixture poured in the water extract with EtOAc then.With the organic phase water and the brine wash that merge, use Na 2SO 4Dry also evaporation.Product is developed and filtered with IPA.Yield 0.92g. 1H-NMR(400MHz；d 6-DMSO)：δ1.35(s，9H)，3.38(m，2H)，4.24(t，2H)，6.92(m，1H)，7.06(d，1H)，7.85(d，1H)，8.19(d，1H)，8.33(dd，1H)，8.70(d，1H)。
E) 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile
In DCM (3ml) solution of 2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) the ethyl carbamic acid tert-butyl ester (0.92g), add 17%HCl-ethanolic soln (10ml) and mixture at room temperature is stirred to raw material and disappear.Throw out is filtered, obtain the 0.70g product, be HCl-salt with diethyl ether washing and drying. 1H-NMR(400MHz；d 6-DMSO)：δ3.31(m，2H)，4.50(t，2H)，7.12(d，1H)，7.99(d，1H)，8.19(d，1H)，8.27-8.35(m，3H)，8.37(dd，1H)，8.73(d，1H)。
F) N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridine-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile (300mg) and 3-(pyridine-2-yl)-1H-pyrazoles-5-formic acid (161mg).Yield 166mg. 1H-NMR(400MHz；d6-DMSO)：δ3.75(q，2H)，4.43(t，2H)，7.09(d，1H)，7.31(b?r.s，1H)，7.39(m，1H)，7.88-7.96(m，3H)，8.20(d，1H)，8.37(dd，1H)，8.47-8.57(m，1H)，8.64(m，1H)，8.71(d，1H)，13.90(m，1H)。
Embodiment 48
3-ethanoyl-N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile (150mg) and 3-ethanoyl-1H-pyrazoles-5-formic acid (94mg).Yield 84mg. 1H-NMR(400MHz；d6-DMSO)：δ3.30(s，3H)，3.71(q，2H)，4.39(t，2H)，7.05(d，1H)，7.27(b?r.s，1H)，7.88(d，1H)，8.18(d，1H)，8.33(d，1H)，8.45-8.75(m，1H)，8.66(d，1H)，14.16(s，1H)。
Embodiment 49
N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-5-methyl different
Figure BDA0000157427790000631
azoles-3-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile (150mg) and 5-methyl different
Figure BDA0000157427790000632
azoles-3-formic acid (89mg).Yield 9mg. 1H-NMR(400MHz；d6-DMSO)：δ2.44(s，3H)，3.70(q，2H)，4.40(t，2H)，6.48(d，1H)，7.05(d，1H)，7.88(d，1H)，8.18(d，1H)，8.32(dd，1H)，8.67(d，1H)，8.79(m，1H)。
Embodiment 50
N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
Title compound utilizes the method preparation of embodiment 34 (d) from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile (50mg) and 3-(pyridin-3-yl)-1H-pyrazoles-5-formic acid (44mg).Yield 27mg. 1H-NMR(400MHz；d6-DMSO)：δ3.74(m，2H)，4.42(t，2H)，7.07(d，1H)，7.17-7.28(m，1H)，7.50(m，1H)，7.90(s，1H)，8.05-8.20(m，2H)，8.31-8.42(m，1H)，8.52-8.59(m，1H)，8.69(d，1H)，8.92-9.04(m，1H)，13.79(s，1H)。
Embodiment 51
3-ethanoyl-N-(2-(3-(3,4-dicyano phenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl) phthalonitrile (50mg) and 3-ethanoyl-1H-pyrazoles-5-formic acid (34mg).Yield 43mg. 1H-NMR(400MHz；d6-DMSO)：δ2.49(s，3H)，3.70(m，2H)，4.37(t，2H)，7.00(d，1H)，7.27(s，1H)，7.86(d，1H)，8.13(d，1H)，8.28(d，1H)，8.45(d，1H)，8.63(br?s，1H)，14.05(br?s，1H)。
Embodiment 52
N-(2-(3-(3,4-dicyano phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d) from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl) phthalonitrile (50mg) and 3-(pyridin-3-yl)-1H-pyrazoles-5-formic acid (42mg).Yield 39mg. 1H-NMR(400MHz；d6-DMSO)：δ3.73(q，2H)，4.40(t，2H)，7.02(d，1H)，7.21(s，1H)，7.49(m，1H)，7.88(s，1H)，8.11-8.16(m，2H)，8.30(dd，1H)，8.40-8.58(m，1H)，8.48(d，1H)，8.56(d，1H)，8.99(s，1H)，13.78(br?s，1H)。
Embodiment 53
N-(2-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 31 with 5-pyridin-3-yl-4H-pyrazoles-3-formic acid (0.46g; 2.43mmol), 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile (0.50g; 2.21mmol), HOBt (0.45g; 3.31mmol), EDCI (0.64g; 3.31mmol) and 0.58ml (3.31mmol) DIPEA prepare as raw material.After the aftertreatment from DCM deposition separate out product and obtain 0.56g (64%) title compound. 1H-NMR (400MHz; D6-DMSO): δ 3.67-3.76 (m, 2H), 4.33-4.41 (m, 2H), 6.85 (d, 1H); 7.22 (s, 1H), 7.49 (dd, 1H), 7.74-7.82 (m, 2H); 7.83 (d, 1H), 7.88 (wide s, 1H), 8.10-8.18 (m, 1H); 8.44-8.58 (m, 2H), 9.00 (wide s, 1H), 13.82 (s, 1H).
Embodiment 54
3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazoles-5-methane amide
With 3-ethanoyl-1H-pyrazoles-5-formic acid (0.469g; 3.04mmol) and 0.8ml DIPEA under nitrogen, be dissolved in 3ml exsiccant DCM.Add HOBt (0.616g; 4.56mmol) and EDCl (0.874g; 4.56mmol).Add 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.75g; 3.04mmol) 4.5ml DCM solution and stirred overnight at room temperature.Add 60ml DCM also with 3x 17ml water washing.The water that merges is washed with 2x 30ml DCM.All DCM washingss are merged and use Na 2SO 4Drying is filtered and evaporation.Product is obtained title compound through carrying out purifying with 2ml EtOH development. 1H-NMR (400MHz; D6-DMSO): δ 2.49 (s, 3H), 3.70 (m, 2H), 4.37 (m, 2H), 6.95 (d, 1H), 7.28 (s, 1H), 7.84 (d, 1H), 7.94, (dd, 1H), 7.98 (d, 1H), 8.07 (d, 1H), 8.64 (wide s, 1H), 14.19 (s, 1H).
Embodiment 55
(R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
Title compound utilizes method that Mitsunobu reaction utilizes embodiment 3 (c) with 2-chloro-4-(1H-pyrazoles-5-yl)-benzonitrile (2.00g; 9.82mmol) and (R)-tertiary butyl 1-hydroxy propane-(1.893g 10.80mmol) prepares as raw material 2-aminocarbamic acid ester.Remove Boc and carry out aftertreatment and obtain 0.434g (17%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ0.97(d，3H)，2.96(m，2H)，4.15(m，2H)，6.98(d，1H)，7.86(d，1H)，7.92-8.00(m，2H)，8.11(d，1H)。
B) (R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method preparation of embodiment 34 (d).With (R)-4-(1-(2-amino-propyl group)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (1.00g, 3.84mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (0.591g; 3.84mmol), 1.0ml DIPEA is dissolved in 3ml exsiccant DCM under nitrogen.Add HOBt (0.777g; 5.75mmol) and EDCI (1.103g; 5.75mmol) and with reaction solution stirred overnight at room temperature.Crude product (576mg) is obtained 164mg (11%) title compound with 4ml EtOH crystallization. 1H-NMR (400MHz; D6-DMSO): δ 1.16 (d, 3H), 2.49 (s, 3H), 4.34-4.38 (m, 2H), 4.40-4.53 (m, 1H), 6.93 (d, 1H), 7.31 (m, 1H), 7.81 (d, 1H), 7.85-8.09 (m, 3H), 8.48 (wide s, 1H), 14.15 (s, 1H).
Embodiment 56
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
With (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide (100mg; 0.25mmol) and 5ml EtOH joins in the reaction flask and slowly add Peng Qinghuana (19mg; 0.5mmol) EtOH suspension-s.Reaction solution stirred overnight to reaction is accomplished.Drip 0.5ml water and 1ml 0.5M HCl.Solution evaporation to doing, is added 20mlDCM and uses 10ml1M NaHCO 3With the 10ml water washing, use Na then 2SO 4Dry.Obtain the pure title compound of 76mg (76%) after filtration and the evaporation. 1H-NMR(400MHz；d6-DMSO)：δ1.11(d，3H)，1.38(d，3H)，4.22-4.48(m，3H)，4.74-4.84(m，1H)，4.41(d，1H)，6.40(s，1H)，6.94(d，1H)，7.81(d，1H)，7.92-8.05(m，2H)，8.09(d，1H)，8.20(d，1H)，13.04(s，1H)。
Embodiment 57
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
This compound utilizes the method preparation of embodiment 34 (d).With (S)-4-(1-(2-amino-propyl group)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (1.00g; 3.84mmol), thiazolamine-4-formic acid (0.66g; 4.66mmol), 1.00ml DIPEA, HOBt (0.26g; 1.9mmol) and EDCI (1.10g; 5.75mmol) as raw material.Through using Virahol: the toluene crystallization is carried out purifying and is obtained 0.93g (63%) title compound. 1H-NMR (400MHz; D6-DMSO): δ 1.10 (d, 3H), 4.22-4.45 (m, 3H), 6.96 (d, 1H), 7.04 (wide s, 2H), 7.15 (s, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 7.97 (s, 1H), 8.08 (s, 1H).
Embodiment 58
(R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide
A) (R)-4-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile hydrochloride
According to the described method of embodiment 3 (c) with 2-chloro-4-(1H-pyrazoles-5-yl) benzonitrile (0.60g, 2.95mmol) with (R)-(0.61g 3.24mmol) carries out Mitsunobu reaction as raw material to tertiary butyl 1-hydroxyl butane-2-aminocarbamic acid ester.Obtain 0.249g (31%) title compound after the aftertreatment. 1H-NMR (400MHz; D6-DMSO): δ 0.91 (t, 3H), 1.22 (d, 3H), 3.33 (wide s, NH 2HCl and water are overlapping) 3.99 (dd, 1H), 4.12 (dd, 1H), 4.44-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.92-7.99 (m, 2H), 8.11 (d, 1H).
B) (R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide
This compound utilizes the method preparation of embodiment 34 (d).Be reflected at and at room temperature use (R)-4-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.249g among the 4ml DCM; 0.91mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (0.140g; 0.91mmol), 0.24ml DIPEA, HOBt (0.184g; 1.36mmol) and EDCI (0.261g; 1.36mmol) spend the night as raw material.Through carrying out purifying with EtOH development. 1H-NMR(400MHz；d6-DMSO)：δ0.90(t，3H)，1.42-1.67(m，2H)，2.51(s，3H)，4.19-4.42(m，3H)，6.91(d，1H)，7.32(s，1H)，7.79(d，1H)，7.85-8.07(m，3H)，8.38(d，1H)，14.14(s，1H)。
Embodiment 59
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
Title compound utilize embodiment 54 method but with 1,3-thiazoles-4-formic acid (149mg; 1.51mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (300mg; 1.51mmol) prepare as raw material.Crude product is carried out purifying through the EtOH development obtain 84mg (20%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.12(d，3H)，4.30-4.53(m，3H)，6.95(d，1H)，7.86(d，1H)，7.95-8.04(m，2H)，8.15(s，1H)，8.28(d，1H)，8.77(d，1H)，9.23(d，1H)。
Embodiment 60
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(4-N-METHYL PIPERAZINE-1-carbonyl)-1H-pyrazoles-5-methane amide
A) (S)-5-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-pyrazoles-3-formic acid
Title compound utilize embodiment 54 method but with 3,5-pyrazoles dioctyl phthalate monohydrate (0.60g; 3.84mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (1.0g; 3.84mmol) prepare as raw material.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-100%MeOH/DCM) obtain 29mg (36%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.14(s，3H)，4.30-4.50(m，3H)，6.93(d，1H)，7.83(s，1H)，7.85-8.05(m，2H)，8.04(s，1H)，8.35-8.65(m，1H)，14.06(s，1H)，14.24(s，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(4-N-METHYL PIPERAZINE-1-carbonyl)-1H-pyrazoles-5-methane amide
With 1-N-METHYL PIPERAZINE (126mg; 1.25mmol) and (S)-5-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-pyrazoles-3-formic acid (50mg; 1.25mmol), HOBt (254mg; 1.88mmol), DIPEA (0.33ml; 1.88mmol) and EDCl (361mg; 1.88mmol) be dissolved in 15ml DCM and stirred overnight at room temperature.Add 50ml DCM also with 3x 15ml water washing.With the water that merges with 2x 20mol DCM washing, with all organic phases merging and use Na 2SO 4Dry.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-20%MeOH/DCM) obtain 75mg (12%) title compound. 1H-NMR (400MHz; D1-CDCl 3): δ 3.90-3.96 (m, 2H), 4.41 (t, 2H), 6.51-6.53 (m, 1H), 6.61 (d, 1H); 6.66 (d, 1H), 6.95 (s, 1H), 7.48-7.50 (m, 2H), 7.61 (wide s, 1H); 7.68 (d, 1H), 7.76-7.79 (m, 1H), 8.11 (s, 1H), 10.45 (wide s, 1H).
Embodiment 61
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
Title compound utilize embodiment 54 method but with 5-pyridin-3-yl-4H-pyrazoles-3-formic acid (181mg; 0.96mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (250mg; 0.96mmol) prepare as raw material.Product precipitates from DCM in last handling process separates out, and it is filtered also obtain the pure title compound of 110mg (27%) after the drying. 1H-NMR(400MHz；d6-DMSO)：δ1.17(s，3H)，4.20-4.60(m，3H)，7.05-7.36(m，1H)，7.40-7.65(m，1H)，7.80-8.60(m，7H)，8.85-9.07(m，1H)，13.76(s，1H)。
Embodiment 62
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
Title compound utilize embodiment 54 method but with thiazole-4-formic acid (50mg; 0.38mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (100mg; 0.38mmol) prepare as raw material.Crude product is passed through chromatogram purification (CombiFlash, silica gel C18 post, eluent: 0-100%ACN/ water) obtain 63mg (44%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.12(d，3H)，4.30-4.52(m，3H)，6.95(d，1H)，7.85(d，1H)，7.95-8.04(m，2H)，8.14(s，1H)，8.27(d，1H)，8.77(d，1H)，9.22(d，1H)。
Embodiment 63
N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl)-2-methylpropane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
A) 2-(1-hydroxy-2-methyl propane-2-yl) xylylenimine-1, the 3-diketone
With 2-amino-2-methyl-1-propanol (4.46g, 50mmol) and Tetra hydro Phthalic anhydride (7.41g is 50mmol) 170 ℃ of down heating 30 minutes.Frozen water is joined in the refrigerative reaction mixture, then mixture is extracted three times with DCM.Organic phase is used Na 2SO 4Drying filters and is evaporated to dried.Crude product is obtained 3.611g (33%) title compound through CombiFlash purifying (post: silica gel, the DCM solution of eluent: 0-10%MeOH).LC-MS：M+1＝220。
B) 4-(1-(2-(1,3-dioxo xylylenimine-2-yl)-2-methyl-propyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile
With 2-(1-hydroxy-2-methyl propane-2-yl) xylylenimine-1,3-diketone (1.10g; 5mmol) with 2-methyl-4-(1H-pyrazole-3-yl) benzonitrile (0.366g; 2.0mmol) under nitrogen, be dissolved in 5ml THF.Add triphenylphosphine (1.05g; 4.0mmol) and DIAD (0.79ml; 4.0mmol) and reaction solution at room temperature stirred weekend.Add triphenylphosphine (0.525g; 2.0mmol) and DIAD (0.39ml; 2.0mmol) and mixture at room temperature stirred 2 days, refluxed then 2 hours.Evaporating solvent adds 50ml water and mixture is washed with 3x 50ml DCM, uses Na 2SO 4Drying filters and is evaporated to dried.Crude mixture is obtained 125mg (16%) title product through CombiFlash purifying twice (post: silica gel, the n-heptane solution of eluent 0-100%EtOAc). 1H-NMR(400MHz；CDCl 3)：δ1.56(s，6H)，2.60(s，3H)，4.2-4.38(m，2H)，6.50(d，1H)，7.33-7.87(m，8H)。
C) 4-(1-(2-amino-2-methyl propyl group)-1H-pyrazole-3-yl)-2-methyl benzonitrile
With 4-(1-(2-(1,3-dioxo xylylenimine-2-yl)-2-methyl-propyl)-1H-pyrazole-3-yl)-2-methyl benzonitrile (0.125g; 0.33mmol) and Hydrazine Hydrate 80 (65%) (0.16ml; 3.3mmol) in 2mlEtOH, stir and refluxed 30 minutes, at room temperature stirred then 2 days.Evaporating solvent adds 5ml water and mixture is washed with 3x10ml 2%MeOH/DCM, uses Na 2SO 4Drying filters and is evaporated to dried.Reaction is not accomplished, and adds reagent and 5 DMF of same amount.Reaction solution is refluxed but not further reaction, and extraction obtains the 80mg product mixtures again as previously mentioned, analyzes based on LC-MS, and it contains 21% title compound.
D) N-(1-(3-(4-cyanic acid-3-aminomethyl phenyl)-1H-pyrazol-1-yl)-2-methylpropane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilize embodiment 54 method but with 5-(2-furyl)-4H-pyrazoles-3-formic acid (56mg; 0.32mmol) and 4-(1-(2-amino-2-methyl propyl group)-1H-pyrazole-3-yl)-2-methyl benzonitrile (80mg; 0.32mmol) prepare as raw material.(eluent: 0-100%ACN/ water) obtain the 16mg product, further (Waters Deltaprep 4000, SymmPrep 56.2,25-80%ACN/AcONH through the preparation HPLC purifying with it for CombiFlash, silica gel-C18 post through chromatogram purification with crude product 4) obtain the 5.3mg title compound. 1H-NMR (400MHz; D1-CDCl 3): δ 1.52 (s, 6H), 2.54 (s, 3H), 4.50 (s, 2H), 6.52 (dd, 1H), 6.57 (d, 1H), 6.64 (d, 1H), 6.90 (s, 1H), 7.44 (d, 1H), 7.48 (d, 1H), 7.59 (d, 1H), 7.70 (dd, 1H), 7.75 (d, 1H), 10.31 (wide s, 1H).
Embodiment 64
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilize embodiment 54 method but with 5-(2-furyl)-4H-pyrazoles-3-formic acid (36mg; 0.20mmol) and 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (50mg; 0.20mmol) prepare as raw material.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-100%MeOH/DCM) obtain 29mg (36%) title compound. 1H-NMR (400MHz; D1-CDCl 3): δ 3.90-3.96 (m, 2H), 4.41 (t, 2H), 6.51-6.53 (m, 1H), 6.61 (d, 1H); 6.66 (d, 1H), 6.95 (s, 1H), 7.48-7.50 (m, 2H), 7.61 (wide s, 1H); 7.68 (d, 1H), 7.76-7.79 (m, 1H), 8.11 (s, 1H), 10.45 (wide s, 1H).
Embodiment 65
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-3-(pyridine-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilize embodiment 53 method but with 5-pyridine-2-base-4H-pyrazoles-3-formic acid (38mg; 0.20mmol) and 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (50mg; 0.20mmol) prepare as raw material.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-100%MeOH/DCM) obtain 19mg (23%) title compound. 1H-NMR (400MHz; D6-DMSO): δ 3.70-3.74 (m, 2H), 4.38 (t, 2H), 6.96 (d, 1H), 7.23-7.40 (m, 2H), 7.82-8.02 (m, 5H), 8.09 (s, 1H), 8.48, (wide s, 1H), 8.62 (d, 1H), 13.89 (wide s, 1H).
Embodiment 66
3-ethanoyl-N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide
Title compound utilize embodiment 20 method but with 3-ethanoyl-1H-pyrazoles-5-formic acid (215mg; 1.37mmol) and 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethylamine hydrochloride (400mg; 1.37mmol) prepare as raw material.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: the 0-100%EtOAc/ heptane) obtain 267mg (50%) title compound. 1H-NMR (400MHz; D6-DMSO): δ 2.50 (s, 3H-and DMSO are overlapping), 2.93 (t, 2H), 3.54-3.60 (m, 2H), 6.33 (d, 1H), 7.02 (d, 1H), 7.30 (s, 1H), 7.58-7.64 (m, 2H), 7.82 (d, 1H), 8.65 (wide s, 1H), 14.21 (s, 1H).
Embodiment 67
(E/Z)-N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-(1-(oxyimino) ethyl)-1H-pyrazoles-5-methane amide
With 3-ethanoyl-N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide (40mg; 0.10mmol) be dissolved in 5ml EtOH.Add anhydrous Na Ac (10mg; 0.12mmol) and hydroxy amine hydrochloric acid salt (8.5mg; 0.12mmol).Reaction mixture is at room temperature stirred 3 days to the reaction completion.Reaction mixture is evaporated to dry doubling is dissolved in 10ml EtOAc, use 2x 2ml water washing then.Use Na 2SO 4Dry and evaporation obtains 34mg (82%) title compound, for the mixture of E and Z isomer ( 1H-NMR/～1: 1). 1H-NMR(400MHz；d1-CDCl 3)：δ2.23/2.26(s，3H)，2.98-3.05(m，2H)，3.72-3.82(m，2H)，6.19-6.32(m，1H)，6.57-6.62(m，1H)，7.01(d，1H)，7.00/7.05(s，1H)，7.20-7.45(m，5H)，7.80/7.86(t，1H)，13.86(s，1H)。
Embodiment 68
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-(1-(the 2-hydroxyethyl is amino) ethyl)-1H-pyrazoles-5-methane amide
With 3-ethanoyl-N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide (78mg; 0.20mmol) and 2-monoethanolamine (10mg; 0.17mmol) be dissolved in 5ml exsiccant toluene and 5ml exsiccant THF and under nitrogen, stirred 6.5 hours down at 75 ℃, stirred overnight at room temperature then.Add Sodium Borohydride (18.8mg; 0.50mmol), at room temperature stirred 3 days, stirred 4.5 hours down at 75 ℃ then.Add the 10mg Sodium Borohydride and mixture is heated 5 hours down to accomplish reaction at 50 ℃.Add 0.1ml water down and pH is adjusted to 1 with 1M HCl at 0 ℃.Solution evaporation to doing, is added 15ml DCM and mixture is used the 10ml water washing.PH is adjusted to 12 and add 15ml DCM with 1M NaOH.Use Na 2SO 4After the drying, (CombiFlash, silicagel column 2.5-10%MeOH/DCM) obtain 19mg (26%) title compound through chromatogram purification with compound. 1H-NMR(400MHz；d1-CDCl 3)：δ1.43(d，3H)，2.55-2.70(m，1H)，2.74-2.85(m，1H)，2.97(t，2H)，3.60-3.76(m，4H)，4.02-4.12(m，1H)，6.16(d，1H)，6.53(d，1H)，6.65(s，1H)，7.33-7.41(m，3H)，7.67(d，1H)。
Embodiment 69
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
Title compound with the form of by product through ((5-(3 for 2-with raw material 3-ethanoyl-N-; The 4-dichlorophenyl) ethyl furans-2-yl))-separation obtains during directly also original preparation N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) the ethyl)-3-of 1H-pyrazoles-5-methane amide (1-(the 2-hydroxyethyl is amino) ethyl)-1H-pyrazoles-5-methane amide.(2.5-10%MeOH/DCM) 21mg (32%) obtains title compound for CombiFlash, silicagel column after carrying out chromatogram purification. 1H-NMR (400MHz; D6-DMSO): δ 1.38 (d, 3H), 2.93 (t, 2H), 3.54 (q, 2H), 4.70-4.85 (m, 1H); 5.42 (s, 1H), 6.33 (d, 1H), 6.43 (s, 1H), 7.02 (d, 1H); 7.55-7.68 (m, 2H), 7.87 (d, 1H), 8.19 (wide s, 1H), 13.03 (s, 1H).
Embodiment 70
N-(2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethyl) pyrazolo [1,5-a] pyrimidine-2-methane amide
Title compound utilize embodiment 20 method but with pyrazolo [1,5-a] pyrimidinecarboxylic acid (82mg; 0.5mmol) and 2-(5-(3, the 4-dichlorophenyl) furans-2-yl) ethylamine hydrochloride (146mg; 0.5mmol) prepare as raw material.Crude product is passed through chromatogram purification (CombiFlash, silicagel column, eluent: 0-20%DCM/MeOH) obtain the 107mg title compound.Product is further obtained 55mg pure products (27%) through carrying out purifying with the toluene development. 1H-NMR(400MHz；d1-CDCl 3)：δ3.06(t，2H)，3.83(m，2H)，6.233(d，1H)，6.61(d，1H)，6.93(dd，1H)，7.35-7.41(m，2H)，7.44(dd，1H)，7.70(d，1H)，8.55(dd，1H)，8.57-8.60(m，1H)。
Embodiment 71
N-(2-(3-(5-chloro-6-cyanopyridine-3-yl)-1H-pyrazol-1-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
A) 3-amino-5-bromo-2-cyanopyridine
(5.0g, (4.56g is in glacial acetic acid 20mmol) (125ml) solution 90mmol) to join 5-bromo-3-nitropyridine-2-formonitrile HCN with iron powder.Suspension-s was stirred 2 hours down at 80 ℃.The refrigerative mixture is filtered and washs with EtOAc through short siliceous earth column.Evaporating solvent is dissolved in resistates EtOAc and uses 20%K 2CO 3Aqueous solution neutralization.Anhydrous Na is used in phase-splitting and with organic phase water and brine wash 2SO 4Drying is filtered and evaporation.Crude product is passed through CombiFlash purifying (DCM-MeOH, gradient elution).Divide merging and evaporation to obtain the 1.67g product product level. 1H-NMR(400MHz；d6-DMSO)：δ6.55(s，2H)，7.46(d，1H，J＝2.0Hz)，7.94(d，1H，J＝1.9Hz)。
B) 5-bromo-3-chloro-2-cyanopyridine
(0.7g, (1.67g, (14ml 169mmol) and in water (4.5ml) suspension-s and at 0-5 ℃ stirred 1 hour down 37% hydrochloric acid 8.43g) 10.15mmol) to join refrigerative 3-amino-5-bromo-2-cyanopyridine with Sodium Nitrite.(0.134g 2.11mmol) and with mixture refluxed 1 hour to add copper powder.With the mixture cooling, alkalize with the frozen water termination reaction and with 48%NaOH.Mixture is extracted with EtOAc.With organic phase water and brine wash, use anhydrous Na 2SO 4Drying is filtered and evaporation obtains the 1.21g product. 1H-NMR(400MHz；d6-DMSO)：δ8.75(d，1H，J＝1.9Hz)，8.90(d，1H，J＝1.9Hz)。
C) 3-chloro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-cyanopyridine
With 5-bromo-3-chloro-2-cyanopyridine (1.68g, 7.73mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl)-(2.47g 8.88mmol) is dissolved in glycol dimethyl ether (25ml) to the 1H-pyrazoles under nitrogen.(0.38g is 0.541mmol) with 2M Na to add two (triphenylphosphine) Palladous chloride 2CO 3(7.73ml 15.45ml) and with mixture stirred 3.5 hours down at 80 ℃ under nitrogen atmosphere.Evaporating solvent extracts resistates with water treatment and with EtOAc.With organic phase water and brine wash, use anhydrous Na 2SO 4Drying is filtered and evaporation.Crude product is obtained the 1.11g product through carrying out purifying with the EtOAc development. 1H-NMR(400MHz；d6-DMSO)：δ1.52-1.63(m，3H)，1.86(m，1H)，1.96(m，1H)，2.35(m，1H)，3.60(m，1H)，3.94(m，1H)，5.39(dd，1H)，6.84(d，1H)，7.69(d，1H)，8.39(d，1H)，8.87(d，1H)。
D) 3-chloro-5-(1H-pyrazoles-5-yl)-2-cyanopyridine
(1.1ml, (1.1g is in absolute ethyl alcohol 3.81mmol) (15ml) solution and at room temperature stirred 3 hours 4.40mmol) to join 3-chloro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-cyanopyridine with the dioxan solution of 4M hydrogenchloride.Evaporating solvent also joins water in the resistates.Mixture is used saturated NaHCO 3Neutralization also extracts with EtOAc.Organic phase is used anhydrous Na 2SO 4Drying is filtered and evaporation obtains the 0.796g product. 1H-NMR(400MHz；d6-DMSO)：δ7.10(d，1H)，7.92(d，1H)，8.58(d，1H)，9.17(d，1H)，13.4(bs，1H)。E) 3-chloro-5-(1-(the 2-trityl is amino) ethyl)-1H-pyrazole-3-yl)-the 2-cyanopyridine
With 3-chloro-5-(1H-pyrazoles-5-yl)-2-cyanopyridine (0.34g; 1.662mmol) join the mineral oil dispersion (0.116g of 60% sodium hydride of cooling (0-5 ℃); 2.91mmol, use heptane wash) exsiccant DMF (8ml) suspension-s in and at room temperature stirred 1 hour.Mixture is cooled to 0-5 ℃ of exsiccant DMF (4ml) solution that also adds 2-bromo-N-trityl ethamine (1.00g, 2.73mmol is according to EP 435749 preparations) gradually also at room temperature to be stirred 3 hours.Mixture is filtered, join in the filtrating water and EtOAc and phase-splitting.Water is extracted with EtOAc,, use anhydrous Na organic phase water and brine wash 2SO 4Drying is filtered and evaporation.Crude product is obtained the 0.56g product through carrying out purifying with heptane-EtOAc development. 1H-NMR(400MHz；d6-DMSO)：δ2.38(m，2H)，2.97(t，1H)，4.29(t，2H)，7.1-7.3(m，16H)，7.98(d，1H)，8.53(d，1H)，9.13(d，1H)。
F) 5-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-3-chloro-2-cyanopyridine
With TFA (3.0ml 40.4mmol) joins refrigerative 3-chloro-5-(1-(2-trityl amino) ethyl)-1H-pyrazole-3-yl)-the 2-cyanopyridine (0.475g, and DCM-MeOH 0.969mmol) (1: 1,6ml) in the solution.Mixture was at room temperature stirred 48 hours, then evaporating solvent.Add entry and ether and phase-splitting.Water is extracted with 2M NaOH alkalization and with DCM.The organic phase that merges is used anhydrous Na 2SO 4Drying is filtered and evaporation obtains the 0.187g product. 1H-NMR(400MHz；d6-DMSO)：δ2.97(t，2H)，4.17(t，2H)，7.07(d，1H)，7.91(d，1H)，8.54(d，1H)，9.13(d，1H)。
G) N-(2-(3-(5-chloro-6-cyanopyridine-3-yl)-1H-pyrazol-1-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
With HOBt hydrate (67mg; 0.437mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (84mg; 0.436mmol) and DIPEA (0.19ml 1.09mmol) joins in DCM (6ml) solution of 5-pyridin-3-yl-4H-pyrazoles-3-formic acid and at room temperature stirred 15 minutes.Add 5-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-3-chloro-2-cyanopyridine and continue stirred overnight.Evaporating solvent adds entry and extracts with EtOAc.Organic phase is used brine wash, use anhydrous Na 2SO 4Drying is filtered and evaporation obtains the 94mg product. 1H-NMR(400MHz；d6-DMSO)：δ3.73(q，2H)，4.41(t，2H)，7.07(d，1H)，7.21(d，1H)，7.49(dd，1H)，7.91(d，1H)，8.13(bs，1H)，8.52(d，1H)，8.55(dd，1H)，8.99(bs，1H)，9.13(d，1H)，13.8(bs，1H)。
Embodiment 72
The 3-tertiary butyl-N-(1-(5-(4-cyanic acid-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) (E)-2-(4-chloro-3-(trifluoromethyl) phenyl)-5-(2-nitro third-1-thiazolinyl) furans
With 5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-formaldehyde (4.00g, 14.5mmol), nitroethane (3.00ml, 40.7mmol), n-butylamine (1.7ml, 17.5mmol) and acetate (7.5ml) mix and to be incorporated in 80 ℃ of heating 2 hours down.After being cooled to room temperature, mixture is filtered.Throw out is obtained the 2.58g title product with alcohol crystal. 1H-NMR(400MHz；d6-DMSO)：δ2.62(s，3H)，7.39(d，1H)，7.57(d，1H)，7.87(m，1H)，8.00(s，1H)，8.11(m，1H)，8.22(m，1H)。
B) 1-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-amine
With (E)-2-(4-chloro-3-(trifluoromethyl) phenyl)-5-(2-nitro third-1-thiazolinyl) furans (2.58g; 7.78mmol) (2.5g is in diethyl ether 65.9mmol) (11ml) solution to mix and be added drop-wise to the lithium aluminum hydride of cooling (20 ℃) with diethyl ether (54ml) and toluene (25ml).Mixture is warming up to 0 ℃ and stirred 3 hours, at room temperature continues then to stir 1 hour.Mixture is cooled off once more and adds down the 2.5ml water at-30 ℃, add the 2.5ml15%NaOH aqueous solution then.Add 7.5ml water and solution is warming up to room temperature.Add MgSO 4, mixture is stirred and filters, throw out is washed with toluene and diethyl ether and filtrating is evaporated to dried.Carry out the CombiFlash purifying, use DCM: MeOH obtains the 1.13g title compound as the eluent system by the level branch that merges. 1H-NMR(400MHz；d6-DMSO)：δ1.01(d，3H)，2.63(m，2H)，3.11-3.15(m，1H)6.28(d，1H)，7.07(d，1H)，7.68(d，1H)，7.87(m，1H)，7.95(m，1H)。
C) the 3-tertiary butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
The 3-tertiary butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide is from 1-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-amine (0.500g; 1.651mmol), the 3-tertiary butyl-1H-pyrazoles-5-formic acid (0.306g; 1.817mmol), HOBt (0.246g; 1.817mmol), DIPEA (0.576ml; 3.303mmol) and EDCI (0.349g 1.817mmol) utilizes the method preparation of embodiment 1 (d), obtains the 0.692g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.19(d，3H)，1.26(s，9H)，2.87-2.92(m，1H)，2.96-3.00(m，1H)，4.29-4.37(m，1H)，6.29-6.32(m，1H)，7.04-7.10(m，1H)，7.57-7.73(m，1H)，7.88-7.98(m，3H)，12.84(m，1H)。
D) the 3-tertiary butyl-N-(1-(5-(4-cyanic acid-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
(0.615g 1.355mmol) weighs and joins in the reaction flask (Biotage) and add 11.6ml DMF with the 3-tertiary butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) propane-2-yl)-1H-pyrazoles-5-methane amide.Add zinc cyanide (0.350g, 2.981mmol), S-Phos (0.112g, 0.271mmol) and Pd2 (dba) 3 (0.100g, 0.108mmol).Reaction flask is used nitrogen wash, and capping was also heated 30 minutes in microwave oven under 150 ℃.Mixture is cooled to room temperature and adds 30ml1MNaOH.Mixture is used water washing with EtOAc extraction 3 times and with the organic layer that merges, use Na 2SO 4Drying filters and is evaporated to dried.Carry out the CombiFlash purifying and obtain the 0.094g title product. 1H-NMR(400MHz；CDCl 3)：δ1.29(d，3H)，1.33(s，9H)，3.00(d，2H)，4.49-4.56(m，1H)，6.31(d，1H)，6.58(s，1H)，6.84(d，1H)，7.11(m，1H)，7.78(m，1H)，7.85(m，1H)，7.95(m，1H)。
Embodiment 73
(E)-N-(2-(5-(4-cyanic acid-3-(trifluoromethyl) phenyl) furans-2-yl) vinyl) pyridine-2-carboxamide
A) (E)-3-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) vinylformic acid
(3.32g 13.4mmol) is dissolved in pyridine (16.6ml) and add piperidines (0.66ml) with 5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-formaldehyde.(1.67g is 1.61mmol) and with reaction mixture refluxed 4 hours to add propanedioic acid.The refrigerative reaction mixture is poured in the solution of ice (100ml), water (100ml) and dense HCl (100ml).Throw out is filtered and uses cold water washing, obtain the 2.55g title compound with ethyl alcohol recrystallization. 1H-NMR(400MHz；d6-DMSO)：δ6.44(d，1H)，7.08(d，1H)，7.40(m，1H)，7.43(d，1H)，7.81(d，1H)，8.14(m，1H)，8.21(m，1H)，12.44(m，1H)。
B) (E)-2-(2-bromo vinyl)-5-(4-chloro-3-(trifluoromethyl) phenyl) furans
With (E)-3-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) vinylformic acid (2.55g; 8.06mmol) join the Dess-Martin Periodinane (18.40ml that is stirring; 59.07mmol) and TEAB (1.84g is in 12.1ml exsiccant DCM solution 8.86mmol).After at room temperature stirring 1.5 hours, reaction mixture with DCM (60ml) dilution and with sodium acid sulfite (10% aqueous solution) solution extraction twice, is used saturated NaHCO 3Aqueous solution extraction twice, the water extracted twice, at last once with the salt solution extraction.Organic layer is used Na2SO 4The dried 2.44g of obtaining title compound is filtered and be evaporated to drying. 1H-NMR(400MHz；d6-DMSO)：δ6.43(d，1H)，7.08(d，1H)，7.67(m，2H)，7.93(m，1H)，8.17(m，2H)。
C) (E)-N-(2-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) vinyl) pyridine-2-carboxamide
With (E)-2-(2-bromo vinyl)-5-(4-chloro-3-(trifluoromethyl) phenyl) furans (0.501g; 1.378mmol) toluene (2.4ml) solution under nitrogen, join inferior ketone (the I) (0.014g of iodate; 0.069mmol), salt of wormwood (0.381g, 2.756mmol), pyridine-2-carboxamide (0.202g, 1.654mmol) and N; (0.0149ml is in mixture 0.0138mmol) for N '-dimethyl-ethylenediamine.With reaction mixture refluxed 7.5 hours and be cooled to room temperature.Wash with EtOAc through one deck filtered through silica gel and with filter cake then.Filtrating is evaporated to dried, uses the CombiFlash purifying, obtain the 0.046g title compound as the eluent system with heptane-DCM. 1H-NMR(400MHz；d6-DMSO)：δ6.54(d，1H)，6.70(d，1H)，7.26(d，1H)，7.61-7.70(m，2H)，7.77(d，1H)，7.99-8.02(m，1H)，8.04-8.09(m，2H)，8.13(m，1H)，8.74(m，1H)，11.20(d，1H)。
D) (E)-N-(2-(5-(4-cyanic acid-3-(trifluoromethyl) phenyl) furans-2-yl) vinyl) pyridine-2-carboxamide
With (E)-N-(2-(5-(4-chloro-3-(trifluoromethyl) phenyl) furans-2-yl) vinyl) pyridine-2-carboxamide (0.046g, 0.012mmol) with zinc cyanide (0.041g, 0.026mmol), S-Phos (0.010g, 0.002mmol) and Pd 2(dba) 3(0.009g 0.001mmol) utilizes the method for embodiment 72 (d) to handle.Obtain the 0.011g title compound through preparation type TLC-purifying. 1H-NMR(400MHz；d6-DMSO)：δ6.63(d，1H)，6.73(d，1H)，7.52(d，1H)，7.68-7.76(m，2H)，8.05-8.21(m，5H)，8.75(d，1H)，11.26(d，1H)。
Embodiment 74
The 3-tertiary butyl-N-(2-(5-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide
A) the 3-tertiary butyl-N-(2-(furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide
With 2-(furans-2-yl) ethamine (0.81g, 7.30mmol) join the 3-tertiary butyl-1H-pyrazoles-5-formic acid of being pre-mixed (10 minutes) (0.61g, 3.60mmol), DCC (1.51g; 7.30mmol) and HOBt (0.99g; 7.30mmol) DCM: DMF solution (10ml, 2: 9, v/v) in the solution.After at room temperature stirring 15 hours, reaction mixture is filtered through Celite pad and with the filtrate water washed twice, is evaporated to dry doubling and obtains the 0.36g title compound with the CombiFlash purifying. 1H-NMR(400MHz；d6-DMSO)：δ1.27(s，9H)，2.84(t，2H)，3.46(m，2H)，6.17(m，1H)，6.35(m，2H)，7.52(m，1H)，8.08(m，1H)，12.89(m，1H)。
B) the 3-tertiary butyl-N-(2-(5-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) furans-2-yl) ethyl)-1H-pyrazoles-5-methane amide
(0.200g 1.20mmol) joins in the solution of water (2ml) and dense HCl (2ml) and with the mixture vigorous stirring, 80 ℃ of heating 15 minutes down, is cooled to-10 ℃ then with 4-amino-2-chloro-3-methyl benzonitrile.(0.091g 1.32mmol) is dissolved in 0.5ml water and being added drop-wise in the refrigerative reaction mixture with Sodium Nitrite.After 40 minutes, mixture is filtered and will be dissolved in the 3-tertiary butyl-N-of acetone (3ml) (2-(furans-2-yl) ethyl)-(0.345g 1.32mmol) joins in the filtrating 1H-pyrazoles-5-methane amide.Drip water (3ml) solution of iron protochloride (II) tetrahydrate then and mixture was at room temperature stirred 15 hours.Water (25ml) is joined in the reaction mixture and with EtOAc extraction three times.The organic layer that merges is used saturated NaHCO 3The aqueous solution and water washing are also used Na 2SO 4Drying filters and is evaporated to dried.Carry out the CombiFlash purifying and obtain the 0.013g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.34(s，9H)，3.03(t，2H)，3.77(m，2H)，6.28(d，1H)，6.62(m，2H)，7.12(m，1H)，7.50(d，1H)，7.65(d，1H)。
Embodiment 75
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methoxy thiazole-2-methane amide
A) 5-methoxy thiazole-2-ethyl formate
(1.00g, 5.29mmol) (1.29g, 5.82mmol) mixture in chloroform (20ml) is 60 ℃ of stirrings 7 hours down with thiophosphoric anhydride with 2-(2-methoxyl group-2-oxoethyl amino)-2-oxo ETHYLE ACETATE.In the refrigerative reaction mixture, add DCM (100ml) and with the washing of mixture water (50ml) and salt solution (50ml).Organic phase is used Na 2SO 4Dry also evaporation.Vaporized residue is dissolved in exsiccant MeCN (10ml) and adds Vanadium Pentoxide in FLAKES (0.75g 5.29mml), refluxes mixture heating up 4.5 hours then.In the refrigerative reaction mixture, add entry (35ml) and mixture is extracted (3x 50ml) with EtOAc.The organic grade of branch that merges used Na 2SO 4Dry and evaporation obtains crude product, and it is passed through twice (the 1st post: silica gel, the n-heptane solution of eluent: 0-100%EtOAc of CombiFlash purifying; Second post: C-18, the aqueous solution of eluent: 0-100%MeCN) obtain 73mg (7%) title compound. 1H-NMR(400MHz；CDCl 3)：δ1.42(t，3H)，4.01(s，3H)，4.43(q，2H)，7.30(s，1H)。
B) 5-methoxy thiazole-2-formic acid
To 5-methoxy thiazole-2-ethyl formate (73mg, add in THF 0.39mmol) (1ml) solution 1M LiOH solution (0.78ml, 0.78mmol).Reaction mixture was at room temperature stirred 1 hour.Be about 5 termination reactions through adding 1M HCl solution to pH.Evaporating solvent, resulting bullion title compound is not purified can be used. 1H-NMR(400MHz；d6-DMSO)：δ3.88(s，3H)，7.12(s，1H)。
C) (R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methoxy thiazole-2-methane amide
(86mg, 0.33mmol) (90mg 0.40mmol) utilizes the method coupling of embodiment 34 (d) with 5-methoxy thiazole-2-formic acid with (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Crude product is obtained 12mg (9%) title compound through CombiFlash purifying (post: silica gel, the DCM solution of eluent: 0-10%MeOH). 1H-NMR (400MHz; CDCl 3): δ 1.23 (d, 3H), 3.99 (s, 3H), 4.26 (dd, 1H), 4.40-4.46 (m, 1H), 4.49-4.59 (m, 1H), 6.63 (d, 1H), 7.22 (s, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.78 (dd, 1H), 8.10 (wide d, and 1H) with 8.13 (d, 1H) overlapping.
Embodiment 76
N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
Title compound is from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.361g; 1.463mmol), 5-pyridin-3-yl-4H-pyrazoles-3-formic acid (0.305g; 1.610mmol), DIPEA (0.382ml, 2.195mmol), HOBt (0.297g, 2.195mmol) and EDCI (0.421g; 2.195mmol) utilize the method for embodiment 75 (b) to prepare, obtain the 0.022g title compound. 1H-NMR(400MHz；d6-DMSO)：δ3.71(m，2H)，4.38(t，2H)，6.97(m，1H)，7.23(m，1H)，7.48(m，1H)，7.86(m，2H)，7.97(m，1H)，8.09(m，1H)，8.17(m，1H)，8.40-8.71(m，2H)，8.98(m，1H)，13.82(m，1H)。
Embodiment 77
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790000831
azoles-3-methane amide
A) 5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790000832
azoles-3-formic acid
(0.436g 2.189mmol) is dissolved in methyl alcohol (20ml) with 5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790000833
azoles-3-ethyl formate.(1.426g, 20ml aqueous solution 4.38mmol) also at room temperature stirred reaction mixture 18 hours to add cesium carbonate.Evaporating solvent also adds the mixture of ETHYLE ACETATE and water in resistates.PH is adjusted to 2.5 also layerings with 10% citric acid solution.Water layer is used Na with ethyl acetate extraction three times and with the organic layer that merges 2SO 4Drying is filtered and evaporation obtains the 0.246g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.49(s，6H)，5.75(m，1H)，6.60(s，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790000834
azoles-3-methane amide
With 5-(2-hydroxy propane-2-yl) different azoles-3-formic acid (0.088g; 0.515mmol) and DIPEA (0.090ml 0.515mmol) is dissolved in 5ml exsiccant DCM.Add anhydrous HOBt (0.070g, 0.515mmol) and EDCI (0.099g, 0.515mmol).(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.112g 0.430mmol) joins in the reaction mixture 2-benzyl chloride nitrile at room temperature to stir (the S)-4-that will be dissolved in 1ml exsiccant DMF after 30 minutes.At room temperature after the stirred overnight; To be dissolved in 5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790000836
azoles-3-formic acid (0.088g of 5ml exsiccant DCM; 0.515mmol), DIPEA (0.090ml; 0.515mmol), anhydrous HOBt (0.070g; 0.515mmol) and EDCI (0.099g, mixture 0.515mmol) joins in the reaction mixture.After 3 hours evaporating solvent and with resistates through the CombiFlash purifying, the DCM solution that utilizes MeOH is as eluent.Divide merging and evaporation to obtain the 58mg product product level. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，1.65(s，6H)，4.26(m，1H)，4.43(m，1H)，4.58(m，1H)，6.60(s，1H)，6.63(d，1H)，7.49(d，1H)，7.68(d，1H)，7.83(d，1H)，7.90(d，1H)，8.07(d，1H)。
Embodiment 78
(S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
A) 2,6-two fluoro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
Title compound is from 4-bromo-2, and 6-difluoro benzonitrile (2.5g, 11.47mmo1) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4; 4,5,5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-yl)-(3.51g 12.61mmol) utilizes the method for embodiment 34 (a) to prepare to the 1H-pyrazoles, generates the 3.61g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.52-1.67(m，3H)，1.81-1.87(m，1H)，1.95-1.99(m，1H)，2.33-2.41(m，1H)，3.59-3.65(m，1H)，3.94-3.98(m，1H)，5.36-5.39(m，1H)，6.77(d，1H)，7.62(s，1H)，7.64(s，1H)，7.66(d，1H)。
B) 2,6-two fluoro-4-(1H-pyrazoles-5-yl) benzonitrile
Title compound is from 2, and (3.32g 11.48mmol) utilizes the method for embodiment 34 (b) to prepare to 6-two fluoro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile, obtains the 2.38g product. 1H-NMR(400MHz；d6-DMSO)：δ7.04(m，1H)，7.83(s，1H)，7.86(s，1H)，7.91(m，1H)，13.37(s，1H)。
C) (S)-and 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2,6-difluoro benzonitrile
Title compound is from 2; 6-two fluoro-4-(1H-pyrazoles-5-yl) benzonitrile (1.39g; 6.78mmol) and (S)-tertiary butyl 1-hydroxy propane-2-aminocarbamic acid ester (1.423g, 8.12mmol), triphenylphosphine (2.129g, 8.12mmol) and DIAD (1.578ml; 8.12mmol) utilize the method for embodiment 34 (c) to prepare, obtain the 0.70g title compound. 1H-NMR(400MHz；d6-DMSO)：δ0.95(d，3H)，3.22(m，1H)，4.01(m，2H)，7.02(d，1H)，7.78(m，1H)，7.81(m，1H)，7.88(d，1H)。
D) (S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2; 6-difluoro benzonitrile (0.7g, 2.67mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (0.494g, 3.20mmol), HOBt (0.433g; 3.20mmol), DIPEA (0.558ml; 3.20mmol) and EDCI (0.614g 3.20mmol) utilizes the method preparation of embodiment 34 (d), obtains the 0.29g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.17(m，3H)，4.32(m，2H)，4.44(m，1H)，6.97(m，1H)，7.31(m，1H)，7.71(m，2H)，7.83(m，1H)，8.44(m，1H)，14.15(m，1H)。
Embodiment 79
N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
A) 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2,6-difluoro benzonitrile
Title compound is from 2; 6-two fluoro-4-(1H-pyrazoles-5-yl) benzonitrile (1.50g; 7.31mmol) and N-(2-hydroxyethyl) t-butyl carbamate (0.96ml, 6.09mmol), triphenylphosphine (1.918g, 7.31mmol) and DIAD (1.200ml; 6.09mmol) utilize the method for embodiment 34 (c) to prepare, obtain the 0.30g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.60(m，2H)，2.94(t，2H)，4.14(t，2H)，7.01(d，1H)，7.79(m，2H)，7.88(d，1H)。
B) N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
Title compound is from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2; 6-difluoro benzonitrile (0.3g, 0.773mmol), 5-pyridin-3-yl-4H-pyrazoles-3-formic acid (0.161g, 0.851mmol), DIPEA (0.202ml; 1.160mmol), HOBt (0.157g; 1.160mmol) and EDCI (0.222g 1.160mmol) utilizes the method preparation of embodiment 34 (d), obtains the 0.06g title compound. 1H-NMR(400MHz；d6-DMSO)：δ3.70(t，2H)，4.39(t，2H)，7.01(d，1H)，7.79(m，2H)，7.88(d，1H)。
Embodiment 80
5-(1H-imidazol-4 yl)-1-methyl-N-(2-(3-(4-nitro-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazole-3-formamide
A) 5-(4-nitro-3-(trifluoromethyl) phenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles
Title compound from 5-bromo-2-nitro-trifluoromethyl toluene (5g, 18.52mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy boron penta ring-2-yl)-(5.67g 20.37mmol) utilizes the method for embodiment 34 (a) to prepare to the 1H-pyrazoles.Reaction obtains the 3.90g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.49-1.68(m，3H)，1.82(m，1H)，1.94(m，1H)，2.38(m，1H)，3.61(m，1H)，3.99(d，1H)，5.31(m，1H)，6.78(d，1H)，7.66(d，1H)，8.10(m，1H)，8.19(m，1H)，8.32(d，1H)。
B) 5-(4-nitro-3-(trifluoromethyl) phenyl)-1H-pyrazoles
(2.693g 7.89mmol) utilizes the method for embodiment 34 (b) to prepare to title compound, obtains the 1.69g title compound from 5-(4-nitro-3-(trifluoromethyl) phenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles. 1H-NMR(400MHz；d6-DMSO)：δ7.08(m，1H)，7.92(m，1H)，8.22(d，1H)，8.35(m，1H)，8.38(m，1H)，13.45(m，1H)。
C) 2-(3-(4-nitro-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) ethamine
(1.69g, 6.57mmol) (1.059g 6.57mmol) utilizes the method for embodiment 34 (c) to prepare to title compound, obtains the 1.24g title compound with 2-hydroxyethyl t-butyl carbamate from 5-(4-nitro-3-(trifluoromethyl) phenyl)-1H-pyrazoles. 1H-NMR(400MHz；d6-DMSO)：δ3.33(m，2H)，4.53(t，2H)，7.13(d，1H)，8.00(d，1H)，8.38(m，1H)，13.45(m，1H)。D) 5-(1H-imidazol-4 yl)-1-methyl-N-(2-(3-(4-nitro-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazole-3-formamide
Title compound is from 2-(3-(4-nitro-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) ethamine (0.062g; 0.208mmol) and 5-(1H-imidazol-4 yl)-1-methyl isophthalic acid H-pyrazoles-3-formic acid (0.05g; 0.260mmol), HOBt (0.035g, 0.260mmol), DIPEA (0.091ml, 0.520mmol) and EDCI (0.050g; 0.260mmol) utilize the method for embodiment 34 (d) to prepare, obtain the 0.128g title compound. 1H-NMR(400MHz；d6-DMSO)：δ3.71(m，3H)，4.40(t，2H)，7.04(s，1H)，7.05(d，1H)，7.88(d，1H)，8.03(s，1H)，8.22(m，1H)，8.31-8.33(m，2H)，8.40(t，1H)，9.03(m，1H)。
Embodiment 81
N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-3-(1-(oxyimino) ethyl)-1H-pyrazoles-5-methane amide
A) 2-nitro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
Title compound from 4-chloro-2-nitrobenzonitrile (3.00g, 16.43mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4; 5; 5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl)-1H-pyrazoles (5.48g; 19.72mmol) utilize the method for embodiment 34 (a) to prepare, obtain the 1.26g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.56-1.62(m，3H)，1.81-1.85(m，1H)，1.95-1.99(m，1H)，2.33-2.47(m，1H)，3.68-3.75(m，1H)，4.01-4.04(m，1H)，5.31-5.34(m，1H)，6.84(d，1H)，7.69(d，1H)，8.13(m，1H)，8.32(d，1H)，8.60(d，1H)。
B) 2-nitro-4-(1H-pyrazoles-5-yl) benzonitrile
(1.26g 4.22mmol) utilizes the method for embodiment 34 (b) to prepare to title compound, obtains the 0.828g title compound from 2-nitro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile. 1H-NMR(400MHz；d6-DMSO)：δ7.09(m，1H)，7.94(m，1H)，8.20(d，1H)，8.37(d，1H)，8.73(s，1H)，13.39(s，1H)。
C) 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile
(0.828g, 3.87mmol) (0.748g 4.64mmol) utilizes the method for embodiment 34 (c) to prepare to title compound, obtains the 0.633g title compound with 2-hydroxyethyl t-butyl carbamate from 2-nitro-4-(1H-pyrazoles-5-yl) benzonitrile. 1H-NMR(400MHz；d6-DMSO)：δ3.21-3.29(m，2H)，4.02-4.04(m，2H)，7.02(d，1H)，7.88(d，1H)，8.13(d，1H)，8.29(m，1H)，8.50(d，1H)。
D) 5-ethanoyl-N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-1H-pyrazole-3-formamide
Title compound is from 4-(1-(2-amino-ethyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile (0.50g; 1.94mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (0.30g; 1.94mmol), HOBt (0.31g, 2.33mmol), DIPEA (0.41ml, 2.33mmol) and EDCI (0.44g; 2.33mmol) utilize the method for embodiment 34 (d) to prepare, obtain the 0.56g title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.48(s，3H)，3.69-3.73(m，2H)，4.39(t，2H)，7.05(d，1H)，7.30(s，1H)，7.88(d，1H)，8.18(d，1H)，8.32(d，1H)，8.66(d，1H)，14.16(s，1H)。E) N-(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-3-(1-(oxyimino) ethyl)-1H-pyrazoles-5-methane amide
(2-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) ethyl)-(0.17g 0.43mmol) is dissolved in ethanol (15ml) to the 1H-pyrazole-3-formamide with 5-ethanoyl-N-.Add sodium acetate (0.071g, 0.86mmol) and hydroxy amine hydrochloric acid salt (0.060g 0.86mmol) and with reaction mixture at room temperature stirred 1.5 hours.Adding pyridine (5ml) continued stirred 65 hours.Reaction mixture is evaporated to dried,, resistates is dissolved in ETHYLE ACETATE with toluene co-evaporated twice.The water washed twice is used Na then 2SO 4Drying is also used the CombiFlash purifying, utilizes DCM and methyl alcohol to obtain the 0.034g title compound as eluent. 1H-NMR(400MHz；d6-DMSO)：δ2.11-2.15(m，3H)，3.68-3.71(m，2H)，4.39(t，2H)，7.05-7.06(m，1H)，7.88(d，1H)，8.17-8.20(m，1H)，8.32-8-35(m，1H)，8.68(d，1H)。
Embodiment 82
(R)-N-(1-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
A) 4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-(trifluoromethyl) benzonitrile
(5.97g 22.6mmol) utilizes the method for embodiment 34 (a) to prepare to title compound, behind column purification, obtains the 5.34g title compound from 4-iodo-2-(trifluoromethyl) benzonitrile.
B) 4-(1H-pyrazoles-5-yl)-2-(trifluoromethyl) benzonitrile
Title compound utilizes the method for embodiment 34 (b) to prepare from 4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-(trifluoromethyl) benzonitrile, obtains the 3.94g title compound. 1H-NMR(400MHz；d6-DMSO)：δ7.07(m，1H)，7.91(m，1H)，8.19(d，1H)，8.31(d，1H)，8.35(s，1H)，13.33(s，1H)。
C) (R)-and 2-(1-N-PROPYLE BROMIDE-2-yl) xylylenimine-1, the 3-diketone
With (R)-2-(1-hydroxy propane-2-yl) xylylenimine-1, (1.3g is 50.0mmol) with phosphorus tribromide (9.2ml, 34mmol) reflux 30 minutes together for the 3-diketone.Reaction mixture is cooled to room temperature and ice is joined in the reaction mixture.After the stirring mixture filtered and just deposition use cold water washing, vacuum-drying to obtain the 12.37g title compound.
D) (R)-4-(1-(2-(1,3-dioxo xylylenimine-2-yl) propyl group)-1H-pyrazole-3-yl)-2-(trifluoromethyl) benzonitrile
With 4-(1H-pyrazoles-5-yl)-2-(trifluoromethyl) benzonitrile (1.0g, 4.22mmol) with (R)-2-(1-N-PROPYLE BROMIDE-2-yl) xylylenimine-1, (1.35g 5.06mmol) weighs and joins in the microwave reaction bottle and add DMF (10ml) the 3-diketone.Add salt of wormwood (1.165g then; 8.43mmol), the inferior ketone (I) of iodate (0.040g, 0.21mmol) and N, N '-dimethyl-ethylenediamine (0.004ml; 0.042mmol) and with reaction flask capping under nitrogen, in microwave oven (Biotage), heated 30 minutes down at 160 ℃ then.Then mixture is poured in the water and with DCM and 2%MeOH/DCM and extracted.Organic layer is merged, use Na 2SO 4Drying filters and is evaporated to dried.Carry out the CombiFlash purifying with positive and reversed-phase column, obtain the 0.199g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.54(m，3H)，4.55-4.65(m，3H)，6.95(d，1H)，7.77(m，4H)，7.82(m，1H)，7.86-7.89(m，2H)，8.01(d，1H)。
E) (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-(trifluoromethyl) benzonitrile
(1-(2-(1,3-dioxo xylylenimine-2-yl) propyl group)-1H-pyrazole-3-yl)-(0.199g 0.469mmol) mixes with ethanol (15ml) 2-(trifluoromethyl) benzonitrile mutually with (R)-4-.(0.227ml 4.69mmol) and with mixture refluxed 3 hours to add Hydrazine Hydrate 80.After being cooled to room temperature, throw out is filtered and uses washing with alcohol.To filtrate and use the CombiFlash purifying, and utilize DCM and methyl alcohol as eluent.Vacuum-drying obtains the 0.080g title product. 1H-NMR(400MHz；d6-DMSO)：δ0.96(d，3H)，3.21-3.29(m，2H)，4.01-4.03(m，2H)，7.05(d，1H)，7.88(d，2H)，8.18(d，1H)，8.26-8.28(m，1H)，8.31(s，1H)。
F) (R)-N-(1-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-(trifluoromethyl) benzonitrile (0.080g; 0.272mg) and 3-(furans-2-yl)-1H-pyrazoles-5-formic acid (0.053g; 0.299mmol) utilize the method for embodiment 34 (d) to prepare, obtain the 0.092g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.17(d，3H)，4.30-4.39(m，2H)，4.42-4.51(m，1H)，6.61(m，1H)，7.03(d，1H)，7.76(m，1H)，7.86(d，1H)，8.17(d，1H)，8.27(m，2H)，8.34-8.36(m，1H)，13.69(m，1H)。
Embodiment 83
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 2-chloro-3-methyl-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
Title compound from 2-chloro-4-iodo-3-methyl benzonitrile (3.52g, 12.68mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-3-(4,4; 5; 5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl)-1H-pyrazoles (3.88g; 13.95mmol) utilize the method for embodiment 34 (a) to prepare, obtain the 2.62g title compound.
B) 2-chloro-3-methyl-4-(1H-pyrazole-3-yl) benzonitrile
(2.62g 8.68mmol) utilizes the method for embodiment 34 (b) to prepare to title compound, obtains the 1.66g title compound from 2-chloro-3-methyl-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile. 1H-NMR(400MHz；d6-DMSO)：δ6.66(t，1H)，7.69(d，1H)，7.84(d，1H)，7.90(m，1H)，13.25(m，1H)。
C) (S)-2-(tert-butoxycarbonyl is amino) propyl group methanesulfonates
(10.25g 58.5mmol) is dissolved in DCM (20ml) with (S)-tertiary butyl 1-hydroxy propane-2-aminocarbamic acid ester.(12.23ml 87.7mmol) and with solution is cooled to 0 ℃ under nitrogen to add triethylamine.(5.0ml 64.3mmol) dilutes with DCM (5ml) and is added drop-wise in the reaction mixture, and temperature is remained on below 10 ℃ with methylsulfonyl chloride.After the adding reaction mixture is warming up to room temperature and continues stirring 36 hours.Next reaction mixture is diluted with DCM (150ml) and use NaHCO 3Solution and water washing are used Na with organic layer for several times 2SO 4Drying is filtered and evaporation obtains the 8.78g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.06(d，3H)，1.38(s，9H)，3.16(s，3H)，3.75(m，1H)，4.04(m，2H)，6.93(m，1H)。
D) (S)-tertiary butyl 1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-aminocarbamic acid ester
(1.96g 8.96mmol) is dissolved in toluene (20ml) with 2-chloro-3-methyl-4-(1H-pyrazole-3-yl) benzonitrile.In this solution, add respectively NaOH the aqueous solution (1M, 20ml) and Tetrabutyl amonium bromide (0.58g, 1.79mmol).(4.54g 17.92mmol) is dissolved in toluene (20ml) and joining in the reaction mixture with (S)-2-(tert-butoxycarbonyl amino) propyl group methanesulfonates.At room temperature vigorous stirring with dilution with toluene and with the water washing several, was used Na with reaction mixture after 96 hours 2SO 4Drying is filtered and evaporation.After utilizing heptane/EtOAc to carry out the CombiFlash purifying, collect and obtain the 1.85g product as eluent. 1H-NMR(400MHz；d6-DMSO)：δ1.02(d，3H)，1.31(s，9H)，2.57(s，3H)，3.91(m，1H)，4.13(m，2H)，6.62(m，1H)，6.87(d，1H)，7.66(d，1H)，7.79(d，1H)，7.84(d，1H)。
E) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile
With (S)-tertiary butyl 1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-aminocarbamic acid ester (1.85g; 4.96mmol) be dissolved in DCM: TFA: water (8: 1.5: 0.5; V: v: v, mixture 20ml) also at room temperature stirred 22 hours.Then reaction mixture is diluted to 50ml and uses NaHCO with DCM 3, salt solution and water washing, organic layer is used Na 2SO 4The dried 1.19g of obtaining title compound is filtered and be evaporated to drying. 1H-NMR(400MHz；d6-DMSO)：δ0.96(d，3H)，2.57(s，3H)，3.23(m，1H)，4.02(d，2H)，6.64(d，1H)，7.67(d，1H)，7.83(d，1H)，7.87(d，1H)。
F) (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (0.2g; 0.728mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (0.112g; 0.728mmol), HOBt (0.128g, 0.946mmol), DIPEA (0.165ml, 0.946mmol) and EDCI (0.181g; 0.946mmol) utilize the method for embodiment 34 (d) to prepare, obtain the 0.117g title compound. 1H-NMR(400MHz；CDCl 3)：δ1.27(d，3H)，2.54(s，3H)，2.55(s，3H)，4.31(m，1H)，4.44(m，1H)，4.62(m，1H)，6.44(d，1H)，7.51(d，1H)，7.54(s，2H)，11.14(m，1H)。
Embodiment 84
N-((S)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
(0.04g 0.097mmol) adds in the ethanol (5ml) (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-the yl)-1H-pyrazoles-5-methane amide that will prepare according to previous embodiment.With solid sodium borohydride (0.018g, 0.487mmol) join in the mixture and with it refluxed under nitrogen 15 minutes.In refrigerative solution, add a 10ml saturated ammonium chloride and mixture is used the DCM extracted several times.Organic extract liquid is merged, use water washing then, use Na 2SO 4The dried 0.040g of obtaining title compound is filtered and be evaporated to drying. 1H-NMR(400MHz；CDCl 3)：δ1.25(m，3H)，1.51(m，3H)，2.49(d，3H)，3.72(m，1H)，4.29(m，1H)，4.41(m，1H)，4.61(m，1H)，4.99(m，1H)，6.42(d，1H)，6.56(s，1H)，7.43-7.50(m，3H)，7.53(d，1H)。
Embodiment 85
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methyl different
Figure BDA0000157427790000931
azoles-3-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (0.2g; 0.728mmol), 5-methyl different
Figure BDA0000157427790000932
azoles-3-formic acid (0.120g; 0.946mmol), HOBt (0.128g; 0.946mmol), DIPEA (0.165ml; 0.946mmol) and EDCI (0.181g 0.946mmol) utilizes DCM to adopt the method preparation of embodiment 34 (d) as solvent, obtains the 0.114g title compound. 1H-NMR(400MHz；CDCl 3)：δ1.26(m，3H)，2.48(d，3H)，2.56(m，3H)，4.29(m，1H)，4.43(m，1H)，4.59(m，1H)，6.41(m，1H)，6.44(d，1H)，7.44(m，1H)，7.50(d，1H)，7.56(d，1H)，7.62(d，1H)。
Embodiment 86
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (0.2g; 0.728mmol), 1,3-thiazoles-4-formic acid (0.113g, 0.874mmol), HOBt (0.118g; 0.874mmol), DIPEA (0.152ml; 0.874mmol) and EDCI (0.167g 0.874mmol) utilizes DCM to adopt the method preparation of embodiment 34 (d) as solvent, obtains the 0.88g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.16(d，3H)，2.51(s，3H)，4.37(m，2H)，6.61(d，1H)，7.67(d，1H)，7.83-7.85(m，2H)，8.27(d，1H)，8.56(d，1H)，9.20(d，1H)。
Embodiment 87
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-formamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (0.15g; 0.546mmol), 5-Trifluoromethyl-1 H-pyrazoles-3-formic acid (0.108g; 0.601mmol), HOBt (0.111g, 0.819mmol), DIPEA (0.143ml, 0.819mmol) and EDCI (0.157g; 0.819mmol) utilize DCM to adopt the method for embodiment 34 (d) to prepare as solvent, obtain the 0.098g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.18(d，3H)，2.48(s，3H)，4.30(m，2H)，4.46(m，1H)，6.60(d，1H)，7.21(m，1H)，7.60(d，1H)，7.79(d，1H)，7.85(d，1H)，8.51(m，1H)，14.39(m，1H)。
Embodiment 88
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (0.059g; 0.331mmol), 3-(furans-2-yl)-1H-pyrazoles-5-formic acid (0.091g; 0.331mmol), HOBt (0.068g, 0.497mmol), DIPEA (0.087ml, 0.497mmol) and EDCI (0.096g; 0.497mmol) utilize DCM to adopt the method for embodiment 34 (d) to prepare as solvent, obtain the 0.065g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.16(d，3H)，2.53(s，3H)，4.28-4.38(m，2H)，4.43-4.51(m，1H)，6.60(d，2H)，6.81-6.91(m，2H)，7.66(d，1H)，7.77(s，1H)，7.82(d，1H)，7.85(m，1H)，8.31(m，1H)，13.69(m，1H)。
Embodiment 89
(R)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
A) (R)-2-(tert-butoxycarbonyl is amino) propyl group methanesulfonates
(9.45g 53.9mmol) utilizes the method for embodiment 83 (c) to prepare to title compound, obtains the 11.48g title compound from (R)-tertiary butyl 1-hydroxy propane-2-aminocarbamic acid ester. 1H-NMR(400MHz；d6-DMSO)：δ1.06(d，3H)，1.38(s，9H)，3.16(s，3H)，3.74(m，1H)，4.04(d，2H)，6.94(m，1H)。
B) (R)-tertiary butyl 1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-aminocarbamic acid ester
(0.5g 2.297mmol) is dissolved in exsiccant acetonitrile (5ml) and be cooled to 0 ℃ under nitrogen with 2-chloro-3-methyl-4-(1H-pyrazole-3-yl) benzonitrile.(0.313g 4.59mmol), stirs reaction mixture 25 minutes and is warming up to room temperature to add sodium ethylate.(0.582g 2.297mmol) is dissolved in 5ml exsiccant acetonitrile and being added drop-wise in the reaction mixture with (R)-2-(tert-butoxycarbonyl amino) propyl group methanesulfonates.With reaction mixture refluxed 15 hours, evaporating solvent then.In resistates, add EtOAc, use saturated NaHCO 3The aqueous solution and water washing are used Na for several times 2SO 4Drying also is evaporated to dried.Utilize heptane/EtOAc system to carry out the CombiFlash purifying and obtain the 0.437g title compound as eluent. 1H-NMR(400MHz；d6-DMSO)：δ1.02(d，3H)，1.31(s，9H)，2.57(s，3H)，3.91(m，1H)，4.13(m，2H)，6.62(m，1H)，6.87(d，1H)，7.66(d，1H)，7.78(d，1H)，7.83(d，1H)。
C) (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile
(0.437g 1.166mmol) utilizes the method for embodiment 83 (e) to prepare to title compound, obtains the 0.306g title compound from (R)-tertiary butyl 1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-aminocarbamic acid ester. 1H-NMR(400MHz；d6-DMSO)：δ0.96(d，3H)，2.57(s，3H)，3.18-3.26(m，1H)，4.01(d，2H)，6.64(d，1H)，7.67(d，1H)，7.83(d，1H)，7.86(d，1H)。
D) (R)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
Title compound is from (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (0.3g; 1.092mmol), 5-pyridin-3-yl-4H-pyrazoles-3-formic acid (0.227g; 1.201mmol), DIPEA (0.285ml, 1.638mmol), HOBt (0.221g, 1.638mmol) and EDCI (0.314g; 1.638mmol) utilize the method for embodiment 34 (d) to prepare, obtain the 0.214g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.15-1.21(m，3H)，2.54(s，3H)，4.28-4.41(m，2H)，4.45-4.54(m，2H)，6.61(d，1H)，7.22(d，1H)，7.45-7.52(m，1H)，7.62-7.70(m，1H)，7.76-1.86(m，2H)，8.09-8.18(m，1H)，8.25-8.47(m，1H)，8.53-8.57(m，1H)，8.99(d，1H)。
Embodiment 90
(R)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (0.077g; 0.280mmol), 3-(furans-2-yl)-1H-pyrazoles-5-formic acid (0.055g; 0.308mmol), DIPEA (0.073ml, 0.420mmol), HOBt (0.057g, 0.420mmol) and EDCI (0.081g; 0.420mmol) utilize the method for embodiment 34 (d) to prepare, obtain the 0.090g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.15-1.17(m，3H)，2.52(s，3H)，4.32-4.35(m，2H)，4.44-4.51(m，1H)，6.61(d，2H)，7.65-7.67(m，1H)，7.75-7.79(m，1H)，7.82(d，1H)，7.84(d，1H)，8.30(m，2H)，8.35(m，2H)，13.69(m，1H)。
Embodiment 91
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-ethyl-1; 2,4-two
Figure BDA0000157427790000961
azoles-5-methane amide
With (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.77mmol) and 3-ethyl-1; 2; (131mg 0.92mmol) utilizes the method coupling of embodiment 34 (d) to 4-
Figure BDA0000157427790000962
diazole-5-formic acid.Crude product is suspended among the MeCN and throw out filtered obtain 34mg (11%) title compound.To filtrate through CombiFlash purifying (post: C-18, eluent: 0-100%MeCN) obtain other 118mg (40%) title product.The total recovery that merges is 152mg (51%). 1H-NMR (400MHz; D6-DMSO): δ 1.18 (d, 3H), 1.26 (t, 3H), 2.81 (q, 2H), 4.31-4.37 (m, 2H), 4.40-4.52 (m, 1H), 6.95 (d, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 8.06 (d, 1H), 9.39 (wide d, 1H).
Embodiment 92
(E)-4-(5-(((the 3-tertiary butyl-1H-pyrazoles-5-carbonyl) diazenyl) methyl)-furans-2-yl)-2-(trifluoromethyl) benzonitrile
A) 4-bromo-2-(trifluoromethyl)-benzonitrile
(5.00g, (1.85g, 10ml aqueous solution 26.8mmol) keep temperature to be lower than 5 ℃ in adition process to drip Sodium Nitrite in the dense hydrogen bromide suspension-s of 25ml 26.8mmol) to cooling and 4-amino-2-(trifluoromethyl) benzonitrile of vigorous stirring.(3.85g also at room temperature stirred 2 hours in the dense hydrogen bromide solution of 30ml 26.8mmol) to pour this mixture into cuprous bromide (I) then.Then reaction mixture is poured in ice-water (300ml) mixture and with ethyl acetate extraction four times.With saturated sodium bicarbonate and water washing, drying also is evaporated to dried with the extraction liquid that merges.Utilize heptane/ETHYLE ACETATE to carry out the Combiflash purifying and obtain the 5.1g title product as the eluent system. 1H-NMR(400MHz；d6-DMSO)：δ8.13(d，1H)，8.18(d，1H)，8.27(s，1H)
B) 4-(5-formylfuran-2-yl)-2-(trifluoromethyl) benzonitrile
To the 5-formylfuran that is stirring-3-boric acid (0.31g; 2.2mmol), palladium (10%) carbon (0.090g) and yellow soda ash (0.85g; 8.0mmol) ethanol (10ml) solution under nitrogen, add 4-bromo-2-(trifluoromethyl) benzonitrile (0.50g, ethanol 0.19mmol) (10ml) solution.With reaction mixture refluxed 2 hours, be cooled to room temperature then and use alcohol dilution.Mixture is filtered through Celite pad, with washing with alcohol and filtrating is evaporated to dried.Utilize heptane/ETHYLE ACETATE to carry out the Combiflash purifying and obtain the 0.20g title compound as the eluent system. 1H-NMR(400MHz；d6-DMSO)：δ7.73(d，1H)，7.76(d，1H)，8.31(m，1H)，8.33(m，1H)，8.39(m，1H)，9.71(s，1H)。
C) (E)-4-(5-(((the 3-tertiary butyl-1H-pyrazoles-5-carbonyl) diazenyl) methyl) furans-2-yl)-2-(trifluoromethyl) benzonitrile
(0.076g adds in 10ml ethanolic soln 0.41mmol) that 4-(5-formylfuran-2-yl)-(0.10g 0.37mmol) and with mixture at room temperature stirred 36 hours 2-(trifluoromethyl) benzonitrile to the 3-tertiary butyl-1H-pyrazoles-5-carbohydrazide.Evaporating solvent is also used the Combiflash purifying with resistates, utilizes DCM/ methyl alcohol as the eluent system, and the level that obtains containing title compound is divided.With the DCM processing product deposition is separated out these grades branch, obtained the 0.048g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.31(s，9H)，6.55(m，1H)，7.12(d，1H)，7.65(d，1H)，8.24(m，2H)，8.28(m，1H)，8.48(m，1H)，11.82(m，1H)，13.07(m，1H)。
Embodiment 93
Pyridine-2-formic acid { 1-[5-(3, the 4-dichlorophenyl) furans-2-yl]-(E)-methylene radical } hydrazides and pyridine-2-formic acid { 1-[5-(3, the 4-dichlorophenyl) furans-2-yl]-(Z)-methylene radical } hydrazides
With the 2-pyridine formyl hydrazine that is stirring (0.29g, 2.11mmol) and 5-(3, the 4-dichlorophenyl) furfural (0.45g, ethanol 1.87mmol) (24ml) solution was refluxed under nitrogen 2.5 hours.Continue to stir down with the solution cooling and at 0 ℃ then.The solid filtering that deposition is separated out also obtains pyridine-2-formic acid with ice-cold washing with alcohol { [5-(3 for 1-; The 4-dichlorophenyl) furans-2-yl]-(Z)-and methylene radical } mixture (Z: E 33: 67) of hydrazides and pyridine-2-formic acid { 1-[5-(3, the 4-dichlorophenyl)-furans-2-yl]-(E)-methylene radical } hydrazides.Isomer is passed through the flash chromatography on silica gel purifying and separates, and (33: 67-0: 100) agent obtains Z isomer as gradient elution, uses CH then at first to utilize heptane/EtOAc 2Cl 2/ MeOH (99.5: 0.5) obtains E isomer as eluent.
Pyridine-2-formic acid-{ 1-[5-(3, the 4-dichlorophenyl) furans-2-yl]-(Z)-methylene radical }-hydrazides: 1H NMR (400MHz, DMSO-d 6): 7.24 (1H, d), 7.49 (1H, d), 7.61 (1H, s), 7.75-7.80 (1H, m), 7.96 (1H, d), 8.12-8.24 (3H, m), 8.27 (1H, d), 8.87 (1H, m), 12.71 (1H, s).
Pyridine-2-formic acid-{ 1-[5-(3, the 4-dichlorophenyl) furans-2-yl]-(E)-methylene radical }-hydrazides: 1H NMR (400MHz, DMSO-d 6): 7.08 (1H, d), 7.33 (1H, d), 7.67-7.70 (1H, m), 7.74 (1H, distored d), 7.79 (1H, distored dd), 8.04 (1H, d), 8.07 (1H, td), 8.14 (1H, distored d), 8.59 (1H, s), 8.73 (1H, d), 12.29 (1H, s).
Embodiment 94
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-methylthiazol-4-yl)-1H-pyrazole-3-formamide
A) 3-(2-methylthiazol-4-yl)-1H-pyrazoles-5-methyl-formiate
(100mg, 0.595mmol) (143mg 0.892mmol) refluxes in chloroform with bromine with 3-ethanoyl-1H-pyrazoles-5-methyl-formiate.Evaporating solvent, (191mg, 0.586mmol) (44mg 0.586mmol) handles in the methyl alcohol that refluxes with thioacetamide with resulting 3-(2,2-two acetyl bromides)-1H-pyrazoles-5-methyl-formiate.Evaporating solvent is dissolved in resistates DCM and uses water washing.Organic phase is used Na 2SO 4Drying is filtered and evaporation obtains 133mg (102%) title compound. 1H-NMR (400MHz; D6-DMSO): δ 2.71 (s, 3H), 3.83 (s, 3H), 7.10 (s, 1H), 7.90 (s, and 1H) 14.0 (wide s, 1H).
B) 3-(2-methylthiazol-4-yl)-1H-pyrazoles-5-formic acid
The 5ml THF and the 1ml MeOH solution of 3-(2-methylthiazol-4-yl)-1H-pyrazoles-5-methyl-formiate (0.586mmol) are at room temperature handled 3 evenings with 2ml1M NaOH solution.Evaporating solvent adds entry and washs with DCM in resistates.With 1M HCl join water to pH be 5.Water is also neutralized with the 1M sodium hydrogen carbonate solution with the DCM washed twice.Water is evaporated from toluene and evaporation residue is suspended among the EtOH.The solid filtering that obtains is thus obtained 151mg (123%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ2.69(s，3H)，6.68(s，1H)，7.60(s，1H)，12.89(bs，1H)。
C) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-methylthiazol-4-yl)-1H-pyrazole-3-formamide
With 3-(2-methylthiazol-4-yl)-1H-pyrazoles-5-formic acid (0.586mmol) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile utilizes the method coupling of embodiment 34 (d).Crude product is obtained 24mg (18%) title compound through CombiFlash purifying (silicagel column, the n-heptane solution of eluent: 50-100%EtOAc). 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，2.77(s，3H)，4.28(dd，1H)，4.44(dd，1H)，4.55-4.67(m，1H)，6.59(d，1H)，7.06(s，1H)，7.38(s，1H)，7.49(d，1H)，7.60(d，1H)，7.74(dd，1H)，7.82(d，1H)，8.06(d，1H)，11.75(bs，1H)。
Embodiment 95
1-(5-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-pyrazole-3-yl) ethyl 2-(dimethylamino) acetic ester
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide (90mg with embodiment 56; 0.225mmol) 2ml DCM solution join N; The N-N-methylsarcosine (47mg, 0.45mmol), DIPEA (0.13ml; 0.75mmol), anhydrous HOBt (61mg, 0.45mmol) and EDCI (87mg is in 2mlDCM suspension-s 0.45mmol).Reaction mixture is at room temperature stirred 3 evenings.With mixture with DCM dilution and use water washing.Organic phase is used Na 2SO 4Drying is filtered and evaporation.Crude product is passed through twice (first post: silica gel, the DCM solution of eluent: 0-10%MeOH of CombiFlash purifying; Second post: aluminum oxide, the DCM solution of eluent: 0-10%MeOH) obtain 26mg (36%) title compound. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，1.66(d，3H)，2.35(d，6H)，3.20(d，2H)，4.25-4.33(m，1H)，4.37-4.45(m，1H)，4.52-4.64(m，1H)，6.00(q，1H)，6.60(m，1H)，6.80(s，1H)，7.50(dd，1H)，7.67(m，1H)，7.74-7.87(m，2H)，8.09(d，1H)，11.6(bs，1H)。
Embodiment 96
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-6-(1H-pyrazol-1-yl) pyridazine-3-methane amide
With 6-(1H-pyrazol-1-yl) pyridazine-3-formic acid (100mg, 0.53mmol) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile is according to the method coupling of embodiment 34 (d).Crude product is passed through twice (first post: silica gel, the n-heptane solution of eluent: 0-100%EtOAc of CombiFlash purifying; Second post: silica gel, the DCM solution of eluent: 0-15%MeOH) obtain 54mg (26%) title compound. 1H-NMR(400MHz；DMSO)：δ1.23(d，3H)，4.35-4.50(m，2H)，4.51-4.64(m，1H)，6.75(dd，1H)，6.94(d，1H)，7.87(d，1H)，7.92-7.98(m，2H)，8.03(dd，2H)，8.30(m，2H)，8.87(d，1H)，9.38(d，1H)。
Embodiment 97
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(2-(dimethylamino) kharophen) thiazole-4-carboxamide
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide (46mg with embodiment 57; 0.12mmol) 1ml DCM solution join N; The N-N-methylsarcosine (25mg, 0.24mmol), DIPEA (0.041ml; 0.24mmol), anhydrous HOBt (32mg, 0.24mmol) and EDCI (46mg is in 1ml DCM suspension-s 0.24mmol).Reaction mixture is at room temperature stirred 3 evenings.With N, N-N-methylsarcosine (25mg), DIPEA (0.021ml), anhydrous HOBt (16mg) and EDCI (23mg) join in the reaction mixture and continue stirred overnight.Add N, N-N-methylsarcosine (25mg), DIPEA (0.082ml) and EDCI (46mg) subsequently 2 days twice.The last reaction reagent that adds is after three days, through adding the DCM termination reaction and using water washing.Organic phase is used Na 2SO 4Drying is filtered and evaporation.Crude product is passed through twice (first post: silica gel, the DCM solution of eluent: 0-10%MeOH of CombiFlash purifying; Second post: silica gel, the n-heptane solution of eluent: 20-100%EtOAc) obtain 3.2mg (6%) title compound. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，2.42(s，6H)，3.25(s，2H)，4.32(dd，1H)，4.42(dd，1H)，4.53-4.63(m，1H)，6.62(d，1H)，7.49(d，1H)，7.62(d，1H)，7.68(d，1H)，7.78(s，1H)，7.82(dd，1H)，7.96(d，1H)。
Embodiment 98
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(cyano methyl) thiazole-4-carboxamide
With 2-(cyano methyl) thiazole-4-formic acid (280mg, 0.10mmol) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile utilizes the method coupling of embodiment 34 (d).Crude product is passed through twice (first post: silica gel, the n-heptane solution of eluent: 0-100%EtOAc of CombiFlash purifying; Second post: C-18 silica gel, the aqueous solution of eluent: 0-100%MeCN) obtain 4.9mg (1%) title compound. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，4.13(s，2H)，4.31(dd，1H)，4.43(dd，1H)，4.55-4.67(m，1H)，6.63(d，1H)，7.49(d，1H)，7.70(d，1H)，7.79(dd，1H)，7.84(d，1H)，7.97(d，1H)，8.12(d，1H)。
Embodiment 99
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide
A) (S)-4-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
With 2-chloro-4-(1H-pyrazole-3-yl) benzonitrile (1.06g, 4.40mmol), N-Boc-(S)-(-)-2-amino-1-butanols (1.0g, 5.28mmol) and triphenylphosphine (1.73g 6.61mmol) is dissolved in 15ml exsiccant THF under nitrogen.Through syringe with DIAD (1.73ml; 8.81mmol) slowly join in the reaction mixture of cooling (0 ℃).At room temperature after the stirred overnight, reaction mixture is evaporated to dried.With vaporized residue be dissolved in 20ml10%HCl (g)/EtOH solution and at room temperature stirred overnight to carry out the Boc-deprotection.Evaporating solvent adds entry and salt solution in evaporation residue.Resulting solution is used the DCM washed twice, through adding 2M NaOH solution alkalization (pH～12) and using the DCM extracted twice.Organic extract liquid is afterwards merged, use Na 2SO 4Drying is filtered and evaporation obtains 568mg (47%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ.0.87-0.94(m，3H)，1.10-1.45(m，2H)，2.97-3.05(m.1H)，4.01(dd，1H)，4.13(dd，1H)，4.68-4.86(m，1H)，6.97(d，1H)，7.86(d，1H)，7.95(dd，1H)，7.97(dd，1H)，8.10-8.12(m，1H)。MS[M+1]：m/z[274.8+1]。
B) (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide
With (S)-4-(1-(2-amino butyl)-1H-pyrazole-3-yl)-(100mg, 0.73mmol) (123mg 0.80mmol) utilizes the method coupling of embodiment 34 (d) to 2-benzyl chloride nitrile with 3-ethanoyl-1H-pyrazoles-5-formic acid.Crude product is passed through twice (first post: silica gel, the DCM solution of eluent: 0-10%MeOH of CombiFlash purifying; Second post: C-18 silica gel, the aqueous solution of eluent: 0-100%MeCN) obtain 72mg (24%) title compound. 1H-NMR(400MHz；d6-CDCl 3/MeOD)：δ1.03(t，3H)，1.50-1.73(m，2H)，2.54(s，3H)，4.30-4.46(m，3H)，6.63(d，1H)，7.42(s，2H)，7.57(d，1H)，7.73(d，1H)，7.84(d，1H)，7.93(s，1H)。
Embodiment 100
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methylthiazol-2-methane amide
With the 5-methyl isophthalic acid, 3-thiazole-2-formic acid (55mg, 0.38mmol) with (R)-(100mg 0.38mmol) utilizes the method coupling of embodiment 34 (d) to 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Crude product is obtained 80mg (54%) title compound through CombiFlash purifying (post: C-18 silica gel, the aqueous solution of eluent: 0-100%MeCN). 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，2.55(d，3H)，4.26(dd，1H)，4.45(dd，1H)，4.51-4.62(m，1H)，6.63(d，1H)，7.49(d，1H)，7.60(dd，1H)，7.68(d，1H)，7.79(dd，1H)，8.13(d，1H)，8.24(d，1H)。
Embodiment 101
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1; 2,5-
Figure BDA0000157427790001031
diazole-3-methane amide
To 1; 2; 5-
Figure BDA0000157427790001032
diazole-3-formic acid (66mg; 0.58mmol) 5ml DCM solution in add anhydrous HOBt (88mg, 0.65mmol) with the PS-carbodiimide (590mg, 0.77mmol).(100mg is 0.38mmol) and with reaction mixture stirred overnight at room temperature to add (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile after 10 minutes.Resin filter is also used the DCM washed twice.To filtrate with 10% Hydrocerol A, 1M NaHCO 3Solution, salt solution and water washing.Organic phase is used Na 2SO 4Drying is filtered and evaporation obtains 111mg (81%) title compound. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，4.25(dd，1H)，4.48(dd，1H)，4.58-4.70(m，1H)，6.66(d，1H)，7.51(d，1H)，7.71(dd，1H)，7.83(dd，1H)，8.01(dd，1H)，8.31(d，1H)，8.65(s，1H)。
Embodiment 102
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
Peng Qinghuana (12mg to cooling (0 ℃); 0.32mmol) 2ml exsiccant EtOH solution in add (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide (66mg, 3ml exsiccant EtOH solution 0.16mmol) of embodiment 99.With reaction mixture stirred overnight at room temperature, then through adding some water termination reactions and adding 0.5M HCl to pH for acid.Evaporating solvent, the DCM solution of adding 5%MeOH is used 1M NaHCO in evaporation residue 3Solution and water washing.Organic phase is used Na 2SO 4Drying is filtered and evaporation obtains 64mg (96%) title compound. 1H-NMR(400MHz；CDCl 3/MeOD)：δ1.00(t，3H)，1.48-1.65(m，5H)，4.29-4.43(m，3H)，4.94(q，1H)，6.59-6.62(m，2H)，7.52(d，1H)，7.67-7.72(m，1H)，7.78-7.82(m，1H)，7.99-8.01(m，1H)。
Embodiment 103
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-methyl isophthalic acid; 2,4-two azoles-5-methane amide
With (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (219mg; 0.84mmol) and the 3-methyl isophthalic acid; 2,4-
Figure BDA0000157427790001042
diazole-5-formic acid utilizes the method coupling of embodiment 34 (d).Crude product is suspended among MeCN and the MeOH.Suspension filtered is obtained 16mg (5%) colorless solid shape title compound.To filtrate through CombiFlash purifying (post: C-18 silica gel, the aqueous solution of eluent: 0-100%MeCN).The level that will contain title compound divide to merge and is suspended among the MeCN.Suspension filtered is obtained 9mg (3%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.19(d，3H)，2.44(s，3H)，4.34(d，2H)，4.39-4.53(m，1H)，6.95(d，1H)，7.84(d，1H)，7.92(dd，1H)，7.98(d，1H)，8.06(d，1H)，9.42(d，1H)。
Embodiment 104
N-((R)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
A) (R)-4-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
(3.00g, 13.3mmol) (2.76g 14.6mmol) utilizes the method for embodiment 99 to react in the presence of triphenylphosphine and DIAD with N-Boc-(R)-(+)-2-amino-1-butanols with 2-chloro-4-(1H-pyrazole-3-yl) benzonitrile.Carry out obtaining 1.48g (41%) title compound behind the Boc-deprotection. 1H-NMR(400MHz；d6-DMSO)：δ.0.87-0.94(m，3H)，1.11-1.40(m，2H)，2.97-3.06(m，1H)，4.01(dd，1H)，4.13(dd，1H)，4.68-4.84(m，1H)，6.96(d，1H)，7.86(d，1H)，7.94(dd，1H)，7.97(dd，1H)，8.09-8.11(m，1H)。MS[M+1]：m/z[274.8+1]。
B) (R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide
With (R)-4-(1-(2-amino butyl)-1H-pyrazole-3-yl)-(300mg, 1.1mmol) (202mg 1.3mmol) utilizes the method coupling of embodiment 34 (d) to 2-benzyl chloride nitrile with 3-ethanoyl-1H-pyrazoles-5-formic acid.Crude product is obtained 225mg (50%) title compound through CombiFlash purifying (post: C-18 silica gel, the aqueous solution of eluent: 0-100%MeCN). 1H-NMR(400MHz；d6-DMSO)：δ0.90(t，3H)，1.43-1.65(m，2H)，2.49(s，3H)，4.22-4.41(m，3H)，6.91(d，1H)，7.32(s，1H)，7.79(d，1H)，7.86-8.05(m，3H)，8.38(d，1H)，14.1(bs，1H)。
C) N-((R)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
(225mg 0.55mmol) utilizes the method for embodiment 102 to handle with Peng Qinghuana with (R)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)-1H-pyrazoles-5-methane amide.Obtain 192mg (85%) title compound thus. 1H-NMR(400MHz；CDCl 3/MeOD)：δ1.00(t，3H)，1.46-1.67(m，5H)，4.28-4.44(m，3H)，4.94(q，1H)，7.61(m，2H)，7.53(d，1H)，7.69(d，1H)，7.80(d，1H)，8.00(d，1H)。
Embodiment 105
(S)-3-ethanoyl-N-(1-(3-(4-cyanic acid-3-(methylthio group) phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-(64mg 0.16mmol) places the microwave bottle to the 1H-pyrazole-3-formamide with (S)-5-ethanoyl-N-.(12.4mg 0.18mmol) and with reaction mixture heats down at 150 ℃ in microwave reactor to add DMF (1ml) and sulfo-sodium methylate.Add sulfo-sodium methylate (being respectively 12.4mg, 5.6mg and 5.6mg) after 30,30 and 20 minutes in heating.Heat altogether after 90 minutes and evaporate DMF, in vaporized residue, add DCM and use water washing.Organic phase is used Na 2SO 4Drying is filtered and evaporation.Resulting crude product is suspended among the MeCN.Suspension filtered is obtained 9mg (14%) colorless solid shape title compound.To filtrate and obtain 13mg (20%) title compound through CombiFlash purifying (post: C-18 silica gel, the aqueous solution of eluent: 0-100%MeCN). 1H-NMR (400MHz; D6-DMSO): δ 1.11-1.20 (m, 3H), 2.49 (s, 3H, overlapping with DMSO), 2.57-2.64 (m, 3H), 4.20-4.55 (m, 3H), 6.91 (s, 1H), 7.31 (s, 1H), 7.62-7.89 (m, 4H), 8.47 (dd, 1H), 14.2 (d, 1H).
Embodiment 106
(S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3-iodophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
A) 2-nitro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
To 4-chloro-2-nitrobenzonitrile (15g, 82mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy boron penta ring-2-yl)-(27.4g adds two (triphenylphosphine) Palladous chloride (II) (1.12g to the 1H-pyrazoles in 300ml DMF solution 99mmol); 1.64mmol), yellow soda ash (22.7g; 0.16mol) and water (30ml).Reaction mixture 90 ℃ of down heating 4.5 hours, is cooled off and pours in the 500ml water.Water is used the EtOAc extracted twice, the organic grade of branch that merges used saturated NaHCO 3Solution and brine wash are used Na 2SO 4Dry also evaporation.Vaporized residue is suspended among the EtOH (100ml), remaining solid filtering is obtained 17.7g (72%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.52-1.68(m，3H)，1.78-1.87(m，1H)，1.91-2.00(m，1H)，2.31-2.47(m，1H)，3.67-3.76(m，1H)，3.99-4.06(m，1H)，5.32(dd，1H)，6.84(d，1H)，7.69(d，1H)，8.13(dd，1H)，8.32(d，1H)，8.60(d，1H)。
B) 2-nitro-4-(1H-pyrazoles-5-yl) benzonitrile
(17.7g adds the dense HCl of 44ml in EtOH 59mmol) (440ml) solution to 2-nitro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile.Reaction mixture was at room temperature stirred 1.5 hours.With mixture pour in the water (1l) and add 2M NaOH solution to pH be 12.Formed throw out is filtered, obtain 11.7g (92%) title compound with water washing and drying. 1H-NMR(400MHz；d6-DMSO)：δ7.09(d，1H)，7.91(d，1H)，8.20(d，1H)，8.37(dd，1H)，8.73(d，1H)，13.4(bs，1H)。
C) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile
(S)-(2.0g 9.3mmol) utilizes the method for embodiment 34 (d) to prepare to 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile from 2-nitro-4-(1H-pyrazoles-5-yl) benzonitrile.Obtain 1.6g (71%) title compound thus. 1H-NMR(400MHz；d6-DMSO)：δ0.98(d，3H)，3.25-3.33(m，1H)，4.01-4.11(m，2H)，7.08(d，1H)，7.90(d，1H)，8.18(d，1H)，8.34(dd，1H)，8.69(d，1H)。
D) (S)-3-ethanoyl-N-(1-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
(400mg, 1.48mmol) (250mg 1.62mmol) utilizes the method coupling of embodiment 34 (d) with 3-ethanoyl-1H-pyrazoles-5-formic acid with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile.Crude product is obtained 295mg (49%) title compound through CombiFlash purifying (post: silica gel, the DCM solution of eluent: 0-10%MeOH). 1H-NMR(400MHz；d6-DMSO)：δ1.18(d，3H)，2.49(s，3H)，4.26-4.55(m，3H)，7.04(d，1H)，7.30(s，1H)，7.86(d，1H)，8.18(d，1H)，8.31(d，1H)，8.50(d，1H)，8.63(s，1H)，14.1(bs，1H)。
E) (S)-3-ethanoyl-N-(1-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
(490mg 2.17mmol) joins cooling (0 ℃) with tin chloride (II) duohydrate
(S)-(295mg is in dense HCl (2ml) solution 0.72mmol) for 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile.With reaction mixture stirred overnight at room temperature.The 1MNaOH that adds small volume is to forming throw out.With solid filtering, obtain 0.263g (965) title compound with water washing and drying. 1H-NMR(400MHz；d6-DMSO)：δ1.14(d，3H)，2.50(s，3H)，4.27(m，2H)，4.45(m，1H)，6.62(d，1H)，7.01(dd，1H)，7.27(d，1H)，7.32(s，1H)，7.38(d，1H)，7.75(d，1H)，8.51(d，1H)。
F) (S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3-iodophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
With Sodium Nitrite (50mg; Under 0 ℃, slowly join (S)-3-ethanoyl-N-(1-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide (250mg in 1ml aqueous solution 0-73mmol); 0.66mmol) water (2ml), sulfuric acid (71 μ l are 1.33mmol) and in MeCN (3ml) solution.Add potassiumiodide (0.22g, 1ml aqueous solution 1.32mmol) after 15 minutes.Reaction mixture was at room temperature stirred 2 hours, pour into then in the 10ml water.With formed throw out filtration and with 10% acidic sulfurous acid sodium solution and water washing.Crude product is obtained 75mg (23%) title compound through CombiFlash purifying (post: silica gel, the DCM solution of eluent: 3-10%MeOH). 1H-NMR(400MHz；MeOD)：δ1.27(d，3H)，2.55(s，3H)，4.35(m，1H)，4.39(m，1H)，4.57(m，1H)，6.63(d，1H)，7.28(br?s，1H)，7.42(s，1H)，7.57(d，1H)，7.66(d，1H)，7.93(br?s，1H)，8.35(s，1H)。
Embodiment 107
N-((S)-1-(3-(4-cyanic acid-3-iodophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
((S)-1-(3-(4-cyanic acid-3-iodophenyl)-1H-pyrazol-1-yl) propane-2-yl)-(65mg 0.13mmol) utilizes the method for embodiment 102 to handle with Peng Qinghuana to 3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide with N-.Crude product is suspended among the MeCN of small volume, remaining solid filtering is obtained 19mg (29%) title compound. 1H-NMR(400MHz；MeOD/CDCl 3)：δ1.05(d，3H)，1.33(d，3H)，4.12-4.19(m，1H)，4.28-4.40(m，1H)，4.70-4.79(m，1H)，6.38-6.48(m，2H)，7.36-7.40(m，1H)，7.44-7.45(m，1H)，7.69-7.75(m，1H)，8.18-8.82(m，1H)。
Embodiment 108
(R)-3-ethanoyl-N-(1-(3-(6-cyanic acid-5-nitropyridine-3-yl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 3-nitro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-cyanopyridine
To 5-bromo-3-nitropyridine-2-formonitrile HCN (2.00g; 8.77mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4,5; 5-tetramethyl--1; 3,2-dioxy boron penta ring-2-yl)-(2.68g adds two (triphenylphosphine) Palladous chloride (II) (0.31g to the 1H-pyrazoles in 10ml ethylene glycol dimethyl ether solution 9.65mmol); 0.44mmol) and 9ml 2M sodium carbonate solution.Reaction mixture was heated 2 hours down at 50 ℃.The refrigerative reaction mixture is filtered, solid is obtained 2.77g (105%) title compound with water washing and vacuum-drying. 1H-NMR(400MHz；d6-DMSO)：δ1.50-1.66(m，3H)，1.81-2.04(m，2H)，2.29-2.47(m，1H)，3.66-3.79(m，1H)，3.97-4.07(m，1H)，5.37(dd，1H)，6.99(d，1H)，7.74(d，1H)，8.92(s，1H)，9.25(s，1H)。
B) 3-nitro-5-(1H-pyrazoles-5-yl)-2-cyanopyridine
3-nitro-5-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-cyanopyridine (8.77mmol) is dissolved in EtOH (15ml) solution and the stirred overnight at room temperature of 10%HCl (g).20ml water is joined in the reaction mixture, and adding saturated sodium bicarbonate solution then is neutral to pH.Formed throw out is filtered, obtain 1.76g (93%) title compound with water washing and vacuum-drying. 1H-NMR(400MHz；d6-DMSO)：δ7.22(m，1H)，7.98(m，1H)，8.99(d，1H)，9.50(d，1H)，13.5(bs，1H)。
C) (R)-5-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-3-nitro-2-cyanopyridine
(R)-5-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-3-nitro-2-cyanopyridine is from 3-nitro-5-(1H-pyrazoles-5-yl)-2-cyanopyridine (0.88g; 4.9mmol) and (R)-(0.86g 4.9mmol) utilizes the method for embodiment 34 (d) to prepare to tertiary butyl 1-hydroxy propane-2-aminocarbamic acid ester.Obtain 0.62g (56%) title compound thus.m/z[273.3+1]。
D) (R)-3-ethanoyl-N-(1-(3-(6-cyanic acid-5-nitropyridine-3-yl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
(0.62g, 1.14mmol) (0.39g 2.50mmol) utilizes the method coupling of embodiment 34 (d) with 3-ethanoyl-1H-pyrazoles-5-formic acid with (R)-5-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-3-nitro-2-cyanopyridine.Crude product is passed through twice (first post: silica gel, the DCM solution of eluent: 0-10%MeOH of CombiFlash purifying; Second post: C-18, the aqueous solution of eluent: 0-100%MeCN) obtain 86mg (19%) title compound. 1H-NMR (400MHz; CDCl 3): δ 1.23 (d, 3H), 2.56 (s, 3H), 4.33 (dd, 1H), 4.55 (dd, 1H), 4.58-4.67 (m, 1H), 6.83-6.86 (m, 1H), 7.29-7.31 (wide s, 1H), 7.65 (d, 1H), 8.91-8.94 (wide s, 1H), 9.64-9.67 (m, 1H).
Embodiment 109
(S)-3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
A) (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
(0.91g, 3.80mmol) (1.00g 5.71mmol) utilizes the method for embodiment 99 to react in the presence of triphenylphosphine and DIAD with N-Boc-(S)-1-amino-2-propyl alcohol with 2-chloro-4-(1H-pyrazole-3-yl) benzonitrile.Carry out obtaining 0.30g (30%) title compound behind the Boc-deprotection. 1H-NMR(400MHz；d6-DMSO)：δ1.43(d，3H)，2.91-3.40(m?1H)，4.29-4.39(m，1H)，4.71-4.85(m，1H)，7.97(d，1H)，7.89(d，1H)，7.96(d，1H)，7.97(d，1H)，8.11(dd，1H)。m/z[260.7+1]。
B) (S)-3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
(217mg, 0.416mmol) (128mg 0.832mmol) utilizes the method coupling of embodiment 34 (d) with 3-ethanoyl-1H-pyrazoles-5-formic acid with (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Crude product is obtained 30mg (18%) title compound through CombiFlash purifying (post: C-18, the aqueous solution of eluent: 0-100%MeCN). 1H-NMR(400MHz；CDCl 3)：δ1.62(d，3H)，2.55(s，3H)，3.74-3.83(m，1H)，3.90-3.99(m，1H)，4.58-4.69(m，1H)，6.61(d，1H)，7.29(bs，1H)，7.50(d，1H)，7.68(d，1H)，7.77(dd，1H)，8.09(s，1H)，11.1(bs，1H)。
Embodiment 110
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-methyl isophthalic acid H-imidazoles-4-methane amide
(200mg, 0.77mmol) (145mg 1.15mmol) utilizes the method coupling of embodiment 34 (d) with 1-methyl isophthalic acid H-imidazoles-4-formic acid with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Crude product is passed through CombiFlash purifying twice (first post: C-18, the aqueous solution of eluent: 0-100%MeCN; Second post: silica gel, eluent 100%DCM) obtain 121mg (43%) title compound altogether. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，3.74(s，3H)，4.27(dd，1H)，4.41(dd，1H)，4.50-4.62(m，1H)，6.61(d，1H)，7.43(d，1H)，7.48(d，1H)，7.50(d，1H)，7.66(d，1H)，7.78(dd，1H)，7.86(d，1H)，8.17(d，1H)。
Embodiment 111
(R)-3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
A) (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
(1.45g, 7.13mmol) (1.50g 8.56mmol) utilizes the method for embodiment 99 to react in the presence of triphenylphosphine and DIAD with N-Boc-(R)-1-amino-2-propyl alcohol with 2-chloro-4-(1H-pyrazole-3-yl) benzonitrile.Carry out obtaining 843mg (45%) title compound behind the Boc-deprotection. 1H-NMR(400MHz；d6-DMSO)：δ1.43(d，3H)，3.53-3.67(m，1H)，4.29-4.38(m，1H)，4.69-4.83(m，1H)，6.96(d，1H)，7.89(d，1H)，7.95(dd，1H)，7.97(dd，1H)，8.10-8.12(m，1H)。m/z[260.7+1]。
B) (R)-3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
(259mg 1.68mmol) utilizes the method coupling of embodiment 34 (d) with (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (1.29mmol) and 3-ethanoyl-1H-pyrazoles-5-formic acid.Crude product is passed through CombiFlash purifying twice (first post: C-18, the aqueous solution of eluent: 0-100%MeCN; Second post: silica gel, the DCM solution of eluent: 0-7%MeOH) obtain 288mg (56%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.49(d，3H)，2.48(s，3H)，3.56-3.73(m，2H)，4.60-4.75(m，1H)，6.94(d，1H)，7.27(bs，1H)，7.87(d，1H)，7.91-8.01(m，2H)，8.08(dd，1H)，8.58(bs，1H)，14.2(bs，1H)。
Embodiment 112
N-((R)-2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-(100mg 0.25mmol) utilizes the method for embodiment 102 to handle with Peng Qinghuana to 1H-pyrazoles-5-methane amide with (R)-3-ethanoyl-N-.Obtain 87mg (87%) thus and obtain title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.37(d，3H)，1.46(d，3H)，3.52-3.72(m，2H)，4.63-4.84(m，2H)，5.40(bs，1H)，6.42(bs，1H)，6.95(d，1H)，7.87(d，1H)，7.99(s，2H)，8.09-8.22(m，2H)，13.0(bs，1H)。
Embodiment 113
(R)-2-(amino methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-imidazoles-5-methane amide
A) (R)-tertiary butyl (5-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-imidazoles-2-yl) methyl carbamate
(108mg, 0.42mmol) (100mg 0.42mmol) utilizes the method coupling of embodiment 34 (d) with 2-(tert-butoxycarbonyl amino methyl)-1H-imidazoles-5-formic acid with (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Obtain the title compound of quantitative yield after the extraction.
B) (R)-2-(amino methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-imidazoles-5-methane amide
With (R)-tertiary butyl (5-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-imidazoles-2-yl) methyl carbamate (0.42mmol) with 10%HCl (g) stirred overnight in EtOH (30ml).Evaporating solvent also adds entry (50ml) in resistates, with DCM washing (3x30ml), make it to be strong basicity through adding 2M NaOH solution.Water is used Na with DCM extraction (3x50ml) and with the organic phase that merges 2SO 4Dry and evaporation obtains 104mg (65%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.08(d，3H)，3.73(s，2H)，4.27(dd，1H)，4.32-4.48(m，2H)，6.95(d，1H)，7.44(s，1H)，7.83(d，1H)，7.94-8.03(m，2H)，8.07(d，1H)，8.10(m，1H)。
Embodiment 114
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyridine-2-carboxamide also
Title compound according to the described method of embodiment 34 (d) with 4,5,6; 7-tetrahydro-pyrazole also [1; 5-a] pyridine-2-formic acid (0.166g, 0.997mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is used purification by flash chromatography.Yield 56.3%. 1H-NMR(400MHz；DMSO-d6)：δ1.09(d，3H)，1.74-1.82(m，2H)，1.94-2.03(m，2H)，2.71-2.78(m，2H)，4.11(t，2H)，4.27(dd，1H)，4.36(dd，1H)，4.39-4.49(m，1H)，6.30(s，1H)，6.95(d，1H)，7.82(d，1H)，7.96-8.01(m，2H)，8.08-8.11(m，1H)，8.16(d，1H)。
Embodiment 115
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyridine-2-carboxamide also
A) 2-(1H-imidazol-4 yl) thiazole-4-ethyl formate
With 1H-imidazoles-4-thioformamide (1g, 7.86mmol) and ethyl bromide acetone (0.987ml 7.86mmol) is dissolved in ethanol (20ml).The mixture that forms was refluxed 1.5 hours.Mixture was kept 1 hour down and filters at 0 ℃.Filtering throw out all contains product with filtrating, with the two evaporation.To filtrate with twice of ethanol development.At last all throw outs are merged.LC-MS：[M+1]＝224.25。
B) 2-(1H-imidazol-4 yl) thiazole-4-formic acid
(1.5g 6.72mmol) is dissolved in THF (10ml) with 2-(1H-imidazol-4 yl) thiazole-4-ethyl formate.(13.44ml 13.44mmol) and with the mixture that forms stirred 4 hours the 1M solution of adding one hydronium(ion) oxidation lithium in suspension-s.Add the 1M solution of 3.36ml one hydronium(ion) oxidation lithium then and mixture is continued stirring 1 hour.With the mixture evaporation, add 10ml water and pH is adjusted to 1 with dense HCl.Throw out is filtered.Filtrating and filtering throw out all contain product.Filtrating is dissolved in toluene and evaporates twice.LC-MS：[M+1]＝196.20。
C) (S)-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-imidazol-4 yl) thiazole-4-carboxamide
Title compound according to the described method of embodiment 34 (d) with 2-(1H-imidazol-4 yl) thiazole-4-formic acid (0.097g, 0.496mmol) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2,6-difluoro benzonitrile (0.1g, 0.381mmol) preparation.Product is used purification by flash chromatography.Yield 44.8%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，4.32(dd，1H)，4.42(dd，1H)，4.57-4.68(m，1H)，6.58(s，1H)，7.42(s，1H)，7.44(s，1H)，7.51(d，1H)，7.65(d，1H)，7.77(d，1H)，7.84(d，1H)，7.98(s，1H)，11.72(bs，1H)。
Embodiment 116
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 4-bromo-3-chloro-5-fluoroaniline
(5.0g adds N-bromo-succinimide (5.9g, MeCN 33mmol) (10ml) suspension-s in MeCN 33mmol) (50ml) solution to the 3-chloro-5-fluoroaniline that cools off (0 ℃).After at room temperature stirring 2 hours, through adding 10%NaHSO 3(50ml) termination reaction.Mixture is concentrated into half the approximately volume, and water (50ml) dilutes and extracts (3x50ml) with EtOAc.The organic phase that merges is used Na 2SO 4Dry and evaporation obtains crude product, and it is obtained 5.5g (74%) title compound through CombiFlash purifying (post: silica gel, the n-heptane solution of eluent: 0-100%EtOAc). 1H-NMR(400MHz；d6-DMSO)：δ5.88(bs，2H)，6.45(dd，1H)，6.64(m，1H)。
B) 4-amino-2-chloro-6-fluorine benzonitrile
With 4-bromo-3-chloro-5-fluoroaniline (2.08g, 9.27mmol) and cuprous cyanide (I) (0.83g, DMF 9.27mmol) (15ml) mixture in microwave reactor 190 ℃ of down heating 1 hour.Reaction mixture is poured in 12% volatile caustic (200ml) and stirred 30 minutes.Formed throw out is filtered, obtain 1.21g (77%) title compound with water washing and vacuum-drying. 1H-NMR(400MHz；d6-DMSO)：δ6.44(dd，1H)，6.60(m，1H)，6.86(bs，2H)。
C) 2-chloro-6-fluoro-4-iodine benzonitrile
To the 4-amino-2-chloro-6-fluorine benzonitrile of cooling (0 ℃) (3.55g, 20.8mmol), sulfuric acid (3.33ml, 62.4mmol), slow adding Sodium Nitrite (1.58g, water 22.9mmol) (10ml) solution in the solution of water (30ml) and MeCN (100ml).(temperature with reaction mixture remains on below 10 ℃ simultaneously for 6.91g, water 41.6mmol) (10ml) solution slowly to add potassiumiodide.After at room temperature stirring 2 hours, be about the half the of original volume through adding entry (100ml) termination reaction and mixture being concentrated into.Mixture with DCM extraction (3x150ml), is used Na with the organic grade of branch that merges 2SO 4Dry and evaporation obtains 4.77g, (81%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ8.06(dd，1H)，8.08(m，1H)。
D) 2-chloro-6-fluoro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile
To 2-chloro-6-fluoro-4-iodine benzonitrile (5.75g, 20.4mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy boron penta ring-2-yl)-1H-pyrazoles (7.39g; 26.6mmol) THF (60ml) solution in add two (triphenylphosphine) Palladous chloride (II) (0.717g, 1.02mmol), yellow soda ash (5.20g, 49.0mmol) and water (20ml).Reaction mixture was heated 2 hours down at 60 ℃, be concentrated into the % volume, dilute with water (40ml) also at room temperature stirred 1 hour.With formed solid filtering and be suspended among the EtOH (30ml).Suspension-s was stirred 1 hour down at-10 ℃, obtain 2.90g (46%) title compound with the throw out filtration and with the EtOH washing. 1H-NMR(400MHz；d6-DMSO)：δ1.49-1.72(m，3H)，1.78-2.03(m，2H)，2.29-2.44(m，1H)，3.56-3.68(m，1H)，3.93-4.03(m，1H)，5.36(dd，1H)，6.78(d，1H)，7.66(d，1H)，7.73(dd，1H)，7.81(m，1H)。
E) 2-chloro-6-fluoro-4-(1H-pyrazoles-5-yl) benzonitrile
(1.09g 3.55mmol) at room temperature stirred 1 hour with 10%HCl (g)/EtOH solution (50ml) with 2-chloro-6-fluoro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile.Pour in the water (50ml) and use reaction mixture into saturated NaHCO 3Solution alkalizes a little.Formed throw out is filtered, obtain 0.74g (94%) title compound with water washing and vacuum-drying. 1H-NMR(400MHz；d6-DMSO)：δ7.06(d，1H)，7.94(dd，1H)，8.05(m，1H)，13.4(bs，1H)。
F) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile
With 2-chloro-6-fluoro-4-(1H-pyrazoles-5-yl) benzonitrile (0.74g, 3.3mmol) with (S)-(-)-the 2-tert-butoxycarbonyl is amino)-(0.88g 5.0mmol) utilizes the method for embodiment 99 to react in the presence of triphenylphosphine and DIAD to the 1-propyl alcohol.Carry out obtaining 0.45g (49%) title compound behind the Boc-deprotection. 1H-NMR(400MHz；d6-DMSO)：δ0.95(d，3H)，3.17-3.28(m，1H)，4.01(dd，2H)，7.03(d，1H)，7.85-7.91(m，2H)，7.99(m，1H)。
G) (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
(0.22g, 0.55mmol) (0.17g 1.11mmol) utilizes the method coupling of embodiment 34 (d) with 3-ethanoyl-1H-pyrazoles-5-formic acid with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile.Crude product is obtained 47mg (21%) title compound through CombiFlash purifying (post: C-18, the aqueous solution of eluent: 0-100%MeCN). 1H-NMR(400MHz；MeOD)：δ1.28(d，3H)，2.51(s，3H)，4.31(dd，1H)，4.41(dd，1H)，4.52-4.61(m，1H)，6.79(d，1H)，7.23(s，1H)，7.67(d，1H)，7.70(d，1H)，7.83(m，1H)。
Embodiment 117
(R)-3-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
A) (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile
With N-t-BOC-(R)-1-amino-2-propyl alcohol (3.22g; 18.4mmol) and triphenylphosphine (4.82g; 18.4mmol) be dissolved in EtOAc (10ml) and join 2-chloro-3-methyl-4-(1H-pyrazole-3-yl) benzonitrile that (2.00g is in EtOAc 9.2mmol) (20ml) solution.With reaction mixture be cooled to 0 ℃ and through syringe slowly add DIAD (3.62ml, 18.4mmol).After at room temperature reacting 20 hours, (5.58ml 184mmol) and with reaction solution continues to stir 20 hours to add entry (10ml) and dense HCl.With the reaction mixture dilute with water, with DCM washing and with organic phase with rare HCl extracted twice.The water that merges is used the DCM washed twice, through adding 50%NaOH solution alkalization (pH 12) and using the DCM extracted twice.The organic phase that merges is used Na 2SO 4Dry and evaporation obtains 0.74g (29%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.43(d，3H)，2.57(s，3H)，4.29-4.38(m，1H)，4.70-4.85(m，2H)，6.63(d，1H)，7.69(dd，1H)，7.82(dd，1H)，7.89(d，1H)。m/z[274.8+1]。
B) (R)-3-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
(300mg, 1.09mmol) (202mg 1.31mmol) utilizes the method coupling of embodiment 34 (d) with 3-ethanoyl-1H-pyrazoles-5-formic acid with (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile.Crude product is obtained 83mg (19%) title compound through CombiFlash purifying (post: C-18, the aqueous solution of eluent: 0-100%MeCN). 1H-NMR(400MHz；CDCl 3)：δ1.62(d，3H)，2.52-2.58(m，6H)，3.79(dd，1H)，3.91(dd，1H)，4.60-4.71(m，1H)，6.92(d，1H)，7.25(s，1H)，7.27-7.29(m，1H)，7.52(d，1H)，7.54-7.60(m，2H)。
Embodiment 118
(R)-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-1-methyl isophthalic acid H-imidazoles-4-methane amide
(300mg, 1.15mmol) (174mg 1.38mmol) utilizes the method coupling of embodiment 34 (d) with 1-methyl isophthalic acid H-imidazoles-4-formic acid with (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Crude product is obtained 61mg (14%) title compound through CombiFlash purifying (post: C-18, the aqueous solution of eluent: 0-100%MeCN). 1H-NMR(400MHz；d6-DMSO)：δ1.45(d，3H)，3.52-3.72(m，4H)，3.67(s，3H)，4.63-4.75(m，1H)，6.95(d，1H)，7.62(dd，1H)，7.89(d，1H)，7.99(s，1H)，8.00(s，1H)，8.10(t，1H)，8.18(t，1H)。
Embodiment 119
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methyl isophthalic acid; 2,4-two
Figure BDA0000157427790001181
azoles-3-methane amide
With (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (573mg; 2.20mmol) and the 5-methyl isophthalic acid; 2; (338mg 2.64mmol) utilizes the method coupling of embodiment 34 (d) to 4-
Figure BDA0000157427790001182
diazole-3-formic acid.Crude product is obtained 125mg (15%) title compound through CombiFlash purifying (post: silica gel, the n-heptane solution of eluent: 0-100%EtOAc). 1H-NMR(400MHz；d6-DMSO)：δ1.61(d，3H)，2.66(s，3H)，4.28-4.39(m，2H)，4.41-4.53(m，1H)，6.95(d，1H)，6.83(d，1H)，7.94(dd，1H)，7.99(dd，1H)，8.09(m，1H)，9.02(d，1H)。
Embodiment 120
(S)-5-((1H-imidazoles-1-yl) methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-2-methane amide
A) 5-(brooethyl) thiazole-2-ethyl formate
(3.00g, 22.5mmol) with 1, (4.86g, exsiccant EtOH (30ml) mixture 22.5mmol) refluxed 3.5 hours and at room temperature stirred 20 hours the 3-dibromoacetone with the thio-oxamide ethyl ester.Evaporating solvent adds entry and obtains crude product with the DCM extracted twice in resistates, it is obtained 842mg (15%) title compound through CombiFlash purifying (post: silica gel, the n-heptane solution of eluent: 10-100%EtOAc). 1H-NMR(400MHz；d6-DMSO)：δ1.34(t，3H)，4.39(q，2H)，4.83(s，2H)，8.16-8.17(m，1H)。
B) 5-((1H-imidazoles-1-yl) methyl) thiazole-2-ethyl formate
(60% oily dispersion liquid, 82mg add imidazoles (93mg, exsiccant DMF (0.5ml) solution 1.37mmol) in exsiccant DMF (2ml) suspension-s 2.05mmol) to the sodium hydride that cools off (0 ℃).Mixture was at room temperature stirred 45 minutes, is cooled to 0 ℃, add then 5-(brooethyl) thiazole-2-ethyl formate be dissolved in dry DMF (2ml) (342mg, 1.37mmol).At room temperature stir after 20 hours the reaction mixture evaporation, in resistates, add DCM solution and with twice of saturated NaCl solution washing.Obtain 143mg (44%) title compound thus. 1H-NMR(400MHz；d6-DMSO)：δ1.32(t，3H)，4.37(q，2H)，5.39(s，2H)，6.91(s，1H)，7.20(s，1H)，7.75(s，1H)，7.93(s，1H)。
C) 5-((1H-imidazoles-1-yl) methyl) thiazole-2-formic acid
(143mg, 0.60mmol) (1.2ml, THF 1.2mmol) (2ml) and MeOH (1ml) solution at room temperature stirred 1.5 hours with 1MLiOH solution with 5-((1H-imidazoles-1-yl) methyl) thiazole-2-ethyl formate.Add 1M HCl and be about 8 to the pH of mixture.Evaporating solvent directly is used for next synthesis step with resulting crude product. 1H-NMR(400MHz；d6-DMSO)：δ5.28(s，2H)，6.92(s，1H)，7.22(s，1H)，7.54(s，1H)，7.79(s，1H)。
D) (S)-5-((1H-imidazoles-1-yl) methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-2-methane amide
(157mg 0.60mmol) utilizes the method coupling of embodiment 34 (d) with 5-((1H-imidazoles-1-yl) methyl) thiazole-2-formic acid (0.60mmol) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Crude product is passed through CombiFlash purifying twice (first post: C-18, the aqueous solution of eluent: 0-100%MeCN; Second post: silica gel, the DCM solution of eluent: 0-8%MeOH) obtain 13mg (5%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.18(d，2H)，4.29-4.52(m，3H)，5.36(s，2H)，6.92(s，1H)，6.94(dd，1H)，7.22(s，1H)，7.71(s，1H)，7.75(s，1H)，7.83(d，1H)，7.90(dd，1H)，7.96(d，1H)，8.04(d，1H)，8.83(d，1H)。
Embodiment 121
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyrazine-2-methane amide
Title compound according to the described method of embodiment 34 (d) with imidazo [1,2-a] pyrazine-2-formic acid (0.163g, 0.997mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is used purification by flash chromatography.Yield 90%. 1H-NMR(400MHz；CDCl 3)：δ1.18(d，3H)，4.35(dd，1H)，4.43(dd，1H)，4.47-4.57(m，1H)，6.93(d，1H)，7.85(d，1H)，7.94-8.00(m，3H)，8.03-8.06(m，1H)，8.47(d，1H)，8.60(dd，1H)，8.73(d，1H)，9.14-9.16(m，1H)。
Embodiment 122
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyridine-3-carboxamide also
Title compound according to the described method of embodiment 34 (d) with 4,5,6; 7-tetrahydro-pyrazole also [1; 5-a] Nicotinicum Acidum (0.127g, 0.767mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.Yield 55.5%. 1H-NMR(400MHz；DMSO-d6)：δ1.12(d，3H)，1.66-1.75(m，2H)，1.85-1.95(m，2H)，2.87(t，2H)，4.02(t，2H)，4.22-4.23(m，2H)，4.32-4.42(m，1H)，6.94(d，1H)，7.72(d，1H)，7.80(d，1H)，7.83(s，1H)，7.91(dd，1H)，7.97(d，1H)，8.06(d，1H)。
Embodiment 123
(S)-5-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001201
azoles-3-methane amide
The method that (S)-5-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001202
azoles-3-methane amide is utilized embodiment 34 (d) is with 5-ethanoyl different azoles-3-formic acid (2.142g; 13.81mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(3g 2.142g) prepares as raw material 2-benzyl chloride nitrile 4-.Through purification by flash chromatography, yield is 30.5% with product. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，2.66(s，3H)，4.26(dd，1H)，4.47(dd，1H)，4.56-4.66(m，1H)，4.65(d，1H)，7.30(s，1H)，7.50(d，1H)，7.71(d，1H)，7.84(dd，1H)，7.08(d，1H)，7.17(d，1H)。
Embodiment 124
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different
Figure BDA0000157427790001211
azoles-3-methane amide
With the N-method that ((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different
Figure BDA0000157427790001212
azoles-3-methane amide utilizes embodiment 34 (d) with 5-(1-hydroxyethyl) different
Figure BDA0000157427790001213
azoles-3-formic acid (2.170g; 13.81mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(3g 11.51mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Through purification by flash chromatography, yield is 46.1% with product. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，1.62(d，3H)，2.30(s，1H)，4.26(dd，1H)，4.43(dd，1H)，4.53-4.64(m，1H)，5.06(q，1H)，6.63(d，1H)，6.64(d，1H)，7.48(d，1H)，7.69(d，1H)，7.84(dd，1H)，7.87(d，1H)，8.05(d，1H)。
Embodiment 125
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
The method that (S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide is utilized embodiment 34 (d) is with 2-bromo-1; 3-thiazole-4-formic acid (0.957g; 4.60mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(1g 3.84mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Yield 62.7%. 1H-NMR(400MHz；CDCl 3)：δ1.32(d，3H)，4.36(dd，1H)，4.46(dd，1H)，4.58-4.63(m，1H)，6.63(d，1H)，7.51(d，1H)，7.65(d，1H)，7.70(d，1H)，7.76(dd，1H)，7.93(d，1H)，7.40(s，1H)。
Embodiment 126
Acetate 1-(3-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) different
Figure BDA0000157427790001214
azoles-5-yl) ethyl ester
With N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different
Figure BDA0000157427790001221
azoles-3-methane amide (28mg; 0.070mmol) and DMAP (0.864mg, 7.00 μ mol) under nitrogen, be dissolved in pyridine.Reaction mixture is cooled to 0 ℃, and (7.51mg 0.074mmol) and with reaction mixture stirred 2 hours to add diacetyl oxide.Evaporating solvent.Yield 82%. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，δ1.64(d，3H)，2.11(s，3H)，4.25(dd，1H)，4.43(dd，1H)，4.54-4.63(m，1H)，6.05(q，1H)，6.63(d，1H)，6.65(d，1H)，7.48(d，1H)，7.70(d，1H)，7.84(dd，1H)，7.89(d，1H)，8.06(d，1H)。
Embodiment 127
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(pyridin-4-yl) thiazole-4-carboxamide
(S)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(pyridin-4-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-(4-pyridyl) thiazole-4-formic acid (0.190g; 0.921mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 47.5%. 1H-NMR(400MHz；MeOD)：δ1.33(d，3H)，4.40(dd，1H)，4.47(dd，1H)，4.60-4.65(m，1H)，6.77(d，1H)，7.63(d，1H)，7.74(d，1H)，7.82(dd，1H)，7.93(d，1H)，8.00(dd，1H)，8.01(dd，1H)，8.30(s，1H)，8.65(dd，1H)，8.66(dd，1H)。
Embodiment 128
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-morpholino thiazole-4-carboxamide
(S)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-morpholino thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-morpholino-1; 3-thiazole-4-formic acid (0.454g; 2.117mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.5g 1.764mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.Yield 5.48%. 1H-NMR(400MHz；DMSO-d6)：δ1.13(d，3H)，3.38-3.43(m，4H)，3.67-3.72(m，4H)，4.27-4.45(m，3H)，6.95(d，1H)，7.40(s，1H)，7.83(d，1H)，7.92(dd，1H)，7.97(d，1H)，7.98(dd，1H)，8.06(d，1H)。
Embodiment 129
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001231
azoles-4-methane amide
(S)-method that 2-amino-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001232
azoles-4-methane amide utilizes embodiment 34 (d) is with 2-amino-1; 3- azoles-4-formic acid (0.037g; 0.288mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.05g 0.192mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Yield 35.7%. 1H-NMR(400MHz；MeOD)：δ1.23(d，3H)，4.30(dd，1H)，4.37(dd，1H)，4.46-4.54(m，1H)，6.77(d，1H)，7.65(s，1H)，7.69(d，1H)，7.79(dd，1H)，7.91(dd，1H)，8.05(dd，1H)。
Embodiment 130
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(piperidin-4-yl) thiazole-4-carboxamide
A) (S)-tertiary butyl 4-(4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) piperidines-1-manthanoate
(S)-method that tertiary butyl 4-(4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) piperidines-1-manthanoate utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (400mg; 1.534mmol) and 2-[1-(tert-butoxycarbonyl) piperidin-4-yl]-1; (479mg 1.534mmol) prepares as raw material 3-thiazole-4-formic acid.Product is passed through purification by flash chromatography twice.Yield 33.9%. 1H-NMR(400MHz；DMSO-d6)：δ1.14(d，3H)，1.41(s，9H)，1.49-1.64(m，2H)，1.98-2.08(m，2H)，2.89(bs，2H)，3.15-3.27(m，1H)，3.96-4.09(m，2H)，4.29-4.52(m，3H)，6.96(s，1H)，7.84(d，1H)，7.92(dd，1H)，7.97(dd，1H)，8.06(dd，1H)，8.10(s，1H)，8.28(d，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(piperidin-4-yl) thiazole-4-carboxamide
With (S)-tertiary butyl 4-(4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) piperidines-1-manthanoate (0.3g, 0.540mmol) and TFA (0.768g 6.73mmol) is dissolved in DCM/TFA/H 2O mixture and stirred overnight.Reaction mixture is diluted with DCM, use saturated Na 2CO 3And water washing.Organic layer is evaporated.Yield 82%. 1H-NMR(400MHz；DMSO-d6)：δ1.24(d，3H)，1.52(dd，1H)，1.58(dd，1H)，1.91-1.97(m，2H)，2.54-2.62(m，2H)，2.97-3.03(d，2H)，3.04-3.11(m，1H)，4.33(dd，1H)，4.41(dd，1H)，4.44-4.51(m，1H)，6.96(d，1H)，7.85(d，1H)，7.94(dd，1H)，7.99(d，1H)，8.07(d，1H)，8.08(s，1H)，8.28(d，1H)。
Embodiment 131
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(methylamino) thiazole-4-carboxamide
A) 2-(methylamino) thiazole-4-formic acid
With 2-methylamino-1,3-thiazoles-4-ethyl formate (300mg, 1.611mmol) be dissolved in the THF/ water mixture and add the 1M Lithium Hydroxide MonoHydrate (3.22ml, 3.22mmol).Reaction mixture was at room temperature stirred 3 hours, be evaporated to the dried title compound that obtains with pH regulator to acidity and with mixture. 1H-NMR(400MHz；DMSO-d6)：δ2.84(s，3H)，7.46(s，1H)，7.90(bs，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(methylamino) thiazole-4-carboxamide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(methylamino) thiazole-4-carboxamide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.389g; 1.343mmol) and 2-(methylamino) thiazole-(255mg 1.612mmol) prepares as raw material 4-formic acid.Product is developed through purification by flash chromatography and with diethyl ether.Yield 8.28%. 1H-NMR(400MHz；DMSO-d6)：δ1.21(d，3H)，2.85(d，3H)，4.28-4.43(m，3H)，6.96(d，1H)，7.18(s，1H)，7.59(q，1H)，7.84(d，1H)，7.91(d，1H)，7.95-7.96(m，2H)，8.08(dd，1H)。
Embodiment 132
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-morpholino thiazole-4-carboxamide
(R)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-morpholino thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-morpholino-1; 3-thiazole-4-formic acid (0.229g; 1.070mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.25g 0.892mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed through purification by flash chromatography and with diethyl ether.Yield 4.91%. 1H-NMR(400MHz；DMSO-d6)：δ1.23(d，3H)，3.38-342(m，4H)，3.δ7-3.71(m，4H)，4.28-4.45(m，3H)，δ.95(d，1H)，7.39(s，1H)，7.83(d，1H)，7.92(dd，1H)，7.96(d，1H)，7.98(dd，1H)，8.06(d，1H)。
Embodiment 133
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(pyridin-3-yl) thiazole-4-carboxamide
(R)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(pyridin-3-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-(3-pyridyl)-1; 3-thiazole-4-formic acid (0.285g; 1.381mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.3g 1.151mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through the purifying with the DCM development.Yield 1.065%. 1H-NMR(400MHz；CDCl 3)：δ1.31(d，3H)，4.34(dd，1H)，4.48(dd，1H)，4.60-470(m，1H)，6.63(d，1H)，7.37(dd，1H)，7.50-7.54(m，2H)，7.80(dd，1H)，7.88(d，1H)，7.98(d，1H)，8.13-8.18(m，2H)，8.73(dd，1H)，9.16(d，1H)。
Embodiment 134
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(tetramethyleneimine-1-ylmethyl) thiazole-4-carboxamide
(R)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(tetramethyleneimine-1-ylmethyl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-tetramethyleneimine-1-ylmethyl-thiazole-4-formic acid (0.244g; 1.151mmol) and (R)-(1-(2-aminopropyl)-1H-azoles-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Crude product is used water washing.Yield 55.7%. 1H-NMR(400MHz；DMSO-d6)：δ1.23(d，3H)，1.72-1.76(m，4H)，2.57-2.61(m，4H)，3.95(s，2H)，4.32(dd，1H)，4.41(dd，1H)，4.41-4.50(m，1H)，6.96(d，1H)，7.85(d，1H)，7.95(dd，1H)，7.98(dd，1H)，8.09(dd，1H)，8.13(s，1H)，8.44(d，1H)。
Embodiment 135
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-methyl isophthalic acid H-pyrazoles-4-yl) thiazole-4-carboxamide
(R)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-methyl isophthalic acid H-pyrazoles-4-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-(1-methyl isophthalic acid H-pyrazoles-4-yl) thiazole-4-formic acid (0.254g; 1.215mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.457mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 76%. 1H-NMR(400MHz；DMSO-d6)：δ1.17(d，3H)，3.90(s，3H)，4.35(dd，1H)，4.42(dd，1H)，4.50(m，1H)，6.96(d，1H)，7.85(d，1H)，7.86(d，1H)，7.93(d，1H)，7.93(dd，1H)，8.05(d，1H)，8.07(s，1H)，8.34(d，1H)，8.34(s，1H)。
Embodiment 136
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-imidazoles-2-methane amide
(S)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-imidazoles-2-methane amide utilizes embodiment 34 (d) is with 1H-imidazoles-2-formic acid (0.206g; 1.841mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.534mmol) prepares as raw material 2-benzyl chloride nitrile 4-.With crude product with 0.1M HCl, 1M NaCO 3, water and brine wash.Yield 76%. 1H-NMR(400MHz；DMSO)：δ1.23(d，3H)，4.31(dd，1H)，4.38(dd，1H)，4.41-4.50(m，1H)，6.94(d，1H)，7.07(s，1H)，7.24(dd，1H)，7.84(d，1H)，7.96(dd，1H)，7.99(dd，1H)，8.17(dd，1H)，8.65(d，1H)，12.95(s，1H)。
Embodiment 137
(R)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
(R)-method that 2-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-acetylthiazole-4-formic acid (0.597g; 3.07mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.8g 3.07mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether, Virahol and DCM respectively.Yield 24.22%. 1H-NMR(400MHz；DMSO-d6)：δ1.19(d，3H)，2.30(s，3H)，4.37(dd，1H)，4.44(dd，1H)，4.47-4.56(m，1H)，6.96(d，1H)，7.87(d，1H)，7.92(dd，1H)，7.97(d，1H)，7.04(d，1H)，8.49(d，1H)，8.61(s，1H)。
Embodiment 138
(R)-ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate
(R)-method that ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate utilizes embodiment 34 (d) is with 2; 4-thiazole dioctyl phthalate 2-ethyl ester (0.528g; 2.62mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.6g 2.186mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 66.3%. 1H-NMR(400MHz；DMSO-d6)：δ1.17(d，3H)，1.34(t，3H)，4.34(dd，1H)，4.39-4.47(m，3H)，4.47-4.56(m，1H)，6.94(d，1H)，7.83(d，1H)，7.95-7.96(m，2H)，8.02(dd，1H)，8.55(s，1H)，8.61(d，1H)。
Embodiment 139
N-((R)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide
(29.3mg 0.773mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.(160mg 0.387mmol) and with reaction mixture slowly is warming up to room temperature, simultaneously stirred overnight to add (R)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide.Crude product is cooled to 0 ℃, evaporates with pH regulator to 6 and with mixture.Add DCM and several methyl alcohol and with crude product with 1M Na2CO3 and water washing.With product with diethyl ether and DCM and heptane development.Yield 33.3%. 1H-NMR(400MHz；DMSO-d6)：δ1.09-1.17(m，3H)，1.45(t，3H)，2.38-4.53(m，3H)，4.92-5.02(m，1H)，6.23(dd，1H)，6.96(dd，1H)，7.85(dd，1H)，7.92-7.97(m，2H)，8.07-8.09(m，1H)，8.10(d，1H)，8.33-8.39(m，1H)。
Embodiment 140
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001281
azoles-4-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001282
azoles-4-methane amide utilizes embodiment 34 (d) is with 4-
Figure BDA0000157427790001283
iminazole acid (0.212g; 1.841mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.534mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 32.9%. 1H-NMR(400MHz；DMSO-d6)：δ1.11(d，3H)，4.31(dd，1H)，4.38(dd，1H)，4.41-4.49(m，1H)，6.95(d，1H)，7.84(d，1H)，7.97-8.01(m，2H)，8.15(dd，1H)，8.52(d，1H)，8.52(d，1H)，8.59(d，1H)。
Embodiment 141
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001284
azoles-4-methane amide
(R)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001285
azoles-4-methane amide utilizes embodiment 34 (d) is with 4-
Figure BDA0000157427790001286
iminazole acid (0.202g; 1.749mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.457mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 45.5%. 1H-NMR(400MHz；DMSO-d6)：δ1.11(d，3H)，4.31(dd，1H)，4.38(dd，1H)，4.41-4.48(m，1H)，6.95(d，1H)，7.84(d，1H)，7.96-8.01(m，2H)，8.15(dd，1H)，8.50(d，1H)，8.54(d，1H)，8.58(d，1H)。
Embodiment 142
(R)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2,5-dimethyl-
Figure BDA0000157427790001291
azoles-4-methane amide
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2; The method that 5-dimethyl- azoles-4-methane amide utilizes embodiment 34 (d) is with 2; 5-dimethyl--1; 3-
Figure BDA0000157427790001293
azoles-4-formic acid (0.254g; 1.749mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.457mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 54.7%. 1H-NMR(400MHz；DMSO-d6)：δ1.08(d，3H)，2.43(d，6H)，4.28(dd，1H)，4.34-4.45(m，2H)，6.96(d，1H)，7.83(d，1H)，7.96-8.01(m，2H)，8.10(dd，1H)，8.23(d，1H)。
Embodiment 143
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2,5-dimethyl-
Figure BDA0000157427790001294
azoles-4-methane amide
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2; The method that 5-dimethyl-
Figure BDA0000157427790001295
azoles-4-methane amide utilizes embodiment 34 (d) is with 2; 5-dimethyl--1; 3-
Figure BDA0000157427790001296
azoles-4-formic acid (0.262g; 1.804mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.504mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 64.7%. 1H-NMR(400MHz；DMSO-d6)：δ1.08(d，3H)，2.43(d，6H)，4.23(dd，1H)，4.34-4.45(m，2H)，6.96(d，1H)，7.83(d，1H)，7.96-8.01(m，2H)，8.10(dd，1H)，8.23(d，1H)。
Embodiment 144
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(hydroxymethyl) thiazole-4-carboxamide
(108mg 2.85mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.(632.8mg 1.426mmol) and with reaction mixture slowly is warming up to room temperature to thiazole-2-manthanoate, simultaneously stirred overnight to add (R)-ethyl-4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl).Crude product is cooled to 0 ℃, evaporates with pH regulator to 6 and with mixture.Add DCM and several ethanol and crude product is used 1M Na 2CO 3And water washing.Last product with diethyl ether and DCM development, is dripped some heptane.Yield 46.6%. 1H-NMR(400MHz；DMSO-d6)：δ1.12(d，3H)，4.31(dd，1H)，4.40(dd，1H)，4.43-4.51(m，1H)，4.78(s，2H)，6.20(s，1H)，6.95(d，1H)，7.84(d，1H)，7.95(dd，1H)，7.98(dd，1H)，8.08(dd，1H)，8.13(s，1H)，8.50(d，1H)。
Embodiment 145
(S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3-p-methoxy-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
A) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile
(S)-method that 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile utilizes embodiment 34 (c) is with 2-nitro-4-(1H-pyrazoles-5-yl) benzonitrile (2.0g; 9.34mmol) and (S)-tertiary butyl 1-hydroxy propane-(1.6g 9.13mmol) prepares as raw material 2-aminocarbamic acid ester.Yield 71.0%.H-NMR(400MHz；DMSO-d6)：0.98(d，3H)，3.23-3.33(m，1H)，4.01-4.12(m，2H)，7.08(d，1H)，7.90(d，1H)，8.19(d，1H)，8.34(dd，1H)，8.69(d，1H)。
B) (S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
(S)-method that 5-ethanoyl-N-(1-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-nitrobenzonitrile (500mg; 1.843mmol) and the 3-ethanoyl-(341mg 2.212mmol) prepares as raw material 1H-pyrazoles-5-formic acid.Product is developed twice with diethyl ether.Yield 42.9%. 1H-NMR(400MHz；DMSO-d6)：δ1.11-1.27(m，3H)，2.48(s，3H)，4.21-4.57(m，3H)，7.03(d，1H)，7.29(s，1H)，7.86(d，1H)，8.09-8.72(m，4H)，14.1(bs，1H)。
C) (S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3-p-methoxy-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
(0.27g 0.663mmol) joins in the flask and uses nitrogen wash with (S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3-nitrophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide.Add exsiccant THF, then through barrier film drip tetrabutyl methanol ammonium hydroxide methanol solution (1.219ml, 0.729mmol).In reaction process, add the methanol solution of 1.754ml tetrabutyl methanol ammonium hydroxide, react stopped reaction after 6 days.Crude product is evaporated and is dissolved in DCM.Mixture is used water washing, dry and evaporation.Evaporation residue is dissolved in 20% methyl alcohol/DCM solvent also to be passed through with the wetting filtered through silica gel of same solvent.Product is developed with a small amount of DCM.Yield 5.00%. 1H-NMR(400MHz；DMSO-d6)：δ1.16(d，3H)，2.5(s，3H)，3.94(s，3H)，4.31(s，2H)，4.40-4.50(m，1H)，6.88(d，1H)，7.31(s，1H)，7.46-7.54(m，2H)，7.71(d，1H)，7.80(d，1H)，8.49(s，1H)，14.12(s，1H)。
Embodiment 146
(R)-methyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl carbamate
A) 2-(methoxycarbonyl is amino) thiazole-4-formic acid
With thiazolamine-4-methyl-formiate (1.0g, 6.32mmol) be dissolved in the exsiccant pyrido at room temperature slowly add methyl-chloroformate (0.733ml, 9.48mmol).With reaction mixture stirred overnight and be evaporated to dried at room temperature.Evaporation residue is dissolved in exsiccant THF/ methyl alcohol (9: 1) mixture, and (3.50ml 3.50mmol) and with reaction mixture at room temperature stirred 4 hours to add the 1M Lithium Hydroxide MonoHydrate.(2.33ml is 2.33mmol) and with the mixture stirred overnight and be evaporated to dried to add the 1M Lithium Hydroxide MonoHydrate.Add DCM and with pH regulator to 3.Product is filtered and vacuum-drying.Yield 76%. 1H-NMR(400MHz；DMSO-d6)：δ3.75(s，3H)，7.95(s，1H)，12.05(s，1H)，12.76(bs，1H)。
B) (R)-methyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl carbamate
(R)-method that methyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl carbamate utilizes embodiment 34 (d) is with 2-(methoxycarbonyl amino) thiazole-4-formic acid (0.36g; 1.460mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.334g 1.217mmol) prepares as raw material 2-chloro-benzonitrile 4-.Product is developed with diethyl ether and DCM respectively.Yield 27.2%. 1H-NMR(400MHz；DMSO-d6)：δ1.13(d，3H)，3.77(s，3H)，4.33(d，1H)，4.34(d，1H)，4.37-4.45(m，1H)，6.96(d，1H)，7.72(s，1H)，7.83(d，1H)，7.87(d，1H)，7.93-7.94(m，2H)，8.04(t，1H)，11.85(s，1H)。
Embodiment 147
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001321
azoles-4-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) azoles-4-methane amide utilizes embodiment 34 (d) is with 4-
Figure BDA0000157427790001323
iminazole acid (0.181g; 1.596mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.430g 1.330mmol) prepares as raw material 2-chloro-3-methyl benzonitrile.Product is passed through purification by flash chromatography.Yield 0.813%. 1H-NMR(400MHz；CDCl 3)：δ1.27(d，3H)，2.57(s，3H)，4.31(dd，1H)，4.43(dd，1H)，4.54-4.63(m，1H)，6.44(d，1H)，7.50(d，1H)，7.51-7.55(m，2H)，7.60(dd，1H)，7.85(d，1H)，8.22(d，1H)。
Embodiment 148
(S)-ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate
(S)-method that ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate utilizes embodiment 34 (d) is with 2; 4-thiazole dioctyl phthalate 2-ethyl ester (0.556g; 2.76mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.6g 2.301mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 51.9%. 1H-NMR(400MHz；DMSO-d6)：δ1.18(d，3H)，1.34(t，3H)，4.34(dd，1H)，4.39-4.46(m，3H)，4.47-4.55(m，1H)，6.94(d，1H)，7.83(d，1H)，7.94-7.96(m，2H)，8.02(t，1H)，8.55(s，1H)，8.60(d，1H)。
Embodiment 149
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(morpholino methyl) thiazole-4-carboxamide
A) 2-(morpholino methyl) thiazole-4-ethyl formate
With 2-chloromethyl-thiazole-4-ethyl formate (500mg, 2.431mmol) and salt of wormwood (504mg, 3.65mmol) be dissolved in exsiccant DMF and add morpholine (0.212ml, 2.431mmol).With reaction mixture stirred overnight at room temperature, with the DCM dilution and use NaHCO 3And water washing.Organic phase is evaporated to the dried title compound (93%) that obtains. 1H-NMR (400MHz; DMSO-d6): δ 1.30 (t, 3H), 2.49-2.54 (m, 4H, overlapping with DMSO), 3.58-3.63 (m, 4H), 3.84 (s, 2H), 4.29 (q, 2H), 8.47 (s, 1H).m/z[256.3+1]。
B) 2-(morpholino methyl) thiazole-4-formate hydrochlorate
With 2-(morpholino methyl) thiazole-4-ethyl formate (578mg, 2.255mmol) be dissolved in THF/ methyl alcohol (9: 1) mixture and slowly add the 1M Lithium Hydroxide MonoHydrate (4.51ml, 4.51mmol).Reaction mixture was at room temperature stirred 1.5 hours, with pH regulator to 2 and mixture is evaporated to dried.Evaporation residue is developed with ethanol.Throw out is filtered and vacuum-drying.Also filtrating is evaporated to the dried crude product that obtains.m/z[228+1]。
C) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(morpholino methyl) thiazole-4-carboxamide
(S)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(morpholino methyl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-(morpholino methyl) thiazole-4-formate hydrochlorate (260mg; 0.982mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(218mg 0.818mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through organic phase with 1MHCl, 1M Na 2CO 3, salt solution and water washing and purifying.Yield 68.7%. 1H-NMR(400MHz；DMSO-d6)：δ1.23(d，3H)，2.50(t，4H；overlap?with?DMSO)，3.61(t，4H)，3.85(d，2H)，4.32(dd，1H)，4.40(dd，1H)，4.43-4.50(m，1H)，6.96(d，1H)，7.84(d，1H)，7.95(dd，1H)，7.98(dd，1H)，8.02(dd，1H)，8.16(s，1H)，8.46(d，1H)。m/z[471.0+1]。
Embodiment 150
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(the 2-methoxy ethyl is amino) thiazole-4-carboxamide
A) (R)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
The method of (R)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide being utilized embodiment 34 (d) is with (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (100mg; 0.384mmol) and 2-bromo-1; (96mg 0.460mmol) prepares as raw material 3-thiazole-4-formic acid.Product is developed with diethyl ether.Yield 55.8%. 1H-NMR(400MHz；CDCl 3)：δ1.12(d，3H)，4.27-4.52(m，3H)，6.97(d，1H)，7.85(d，1H)，8.00(s，2H)，8.07(s，1H)，8.23(s，1H)，8.64(d，1H)。
B) (R)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
With (R)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide (71mg 0.158mmol) joins in the microwave bottle, with the exsiccant pyridine as solvent.Mixture is used nitrogen bubble.(0.021ml 0.236mmol) and with mixture heats down at 120 ℃ with microwave to add 2-methoxy ethyl amine.In ensuing several days, add 0.133ml 2-methoxyl group-ethylamine altogether and reaction mixture was heated 3-12 hour at every turn.Product is passed through purification by flash chromatography.Yield 29.0%. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，3.40-3.46(m，5H)，3.58(t，2H)，4.29(dd，1H)，4.40(dd，1H)，4.50-4.57(m，1H)，5.38(t，1H)，6.62(d，1H)，7.32(d，1H)，7.49(d，1H)，7.68(d，1H)，7.69(d，1H)，7.83(dd，1H)，7.98(d，1H)。
Embodiment 151
N-((R)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(3-hydroxyl butane-2-base is amino) thiazole-4-carboxamide
A) 2-(3-hydroxyl butane-2-base is amino) thiazole-4-methyl-formiate
With thiazolamine-4-methyl-formiate (1.0,6.32mmol), 3-hydroxyl-2-butanone (1.045ml, 12.01mmol) and acetate (2.278g 37.9mmol) is dissolved in 1, the 2-ethylene dichloride.(3.75g is 17.70mmol) and with the reaction mixture stirred overnight to add sodium triacetoxy borohydride.Add sodium triacetoxy borohydride (3.1g) in two batches and reaction mixture is stirred 2 evenings.Slowly add 1MNaHCO 3And mixture used the DCM extracted twice.The dry mutually also evaporation of DCM is obtained 68.1% title product.m/z[230.3+1]。
B) 2-(3-hydroxyl butane-2-base is amino) thiazole-4-formic acid
With 2-(3-hydroxyl butane-2-base amino) thiazole-4-methyl-formiate (1.092g, 4.75mmol) be dissolved in THF/ water (9: 1) mixture and slowly add the 1M Lithium Hydroxide MonoHydrate (9.49ml, 9.49mmol).Reaction mixture was at room temperature stirred 1 hour and is evaporated to dried.Add DCM and water and with pH regulator to 2.With acid water with the DCM washed twice and be evaporated to dried.Vaporized residue is dissolved in ethanol, is evaporated to the dried crude product that obtains with the throw out filtration and with filtrating.m/z[216.3+1]。
C) N-((R)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(3-hydroxyl butane-2-base is amino) thiazole-4-carboxamide
N-((R)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(3-hydroxyl butane-2-base is amino) thiazole-4-carboxamide utilizes the method for embodiment 34 (d) with 2-(3-hydroxyl butane-2-base is amino) thiazole-4-formic acid (1.35g; 6.24mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(1.356g 5.20mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.Yield 14.45%. 1H-NMR(400MHz；DMSO-d6)：δ0.98-1.19(m，9H)，3.57-3.72(m，2H)，4.23-4.47(m，3H)，4.67(d，1H)，6.94-6.97(m，1H)，7.11-7.14(m，1H)，7.37-7.53(m，1H)，7.69-7.80(m，1H)，7.80-7.85(m，1H)，7.90-8.00(m，2H)，8.06-8.09(m，1H)。
Embodiment 152
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(hydroxymethyl) thiazole-4-carboxamide
A) (S)-ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate
(S)-method that ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (600mg; 2.301mmol) and 2; (556mg 2.76mmol) prepares as raw material 4-thiazole dioctyl phthalate 2-ethyl ester.Product is developed with diethyl ether.Yield 51.9%. 1H-NMR(400MHz；DMSO-d6)：δ1.18(d，3H)，1.34(t，3H)，4.29-4.58(m，5H)，6.97(d，1H)，7.83(d，1H)，7.94-7.96(m，2H)，8.02(t，1H)，8.55(s，1H)，8.60(d，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(hydroxymethyl) thiazole-4-carboxamide
(86mg 2.262mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.(502mg 1.131mmol) and with reaction mixture slowly is warming up to room temperature to thiazole-2-manthanoate, simultaneously stirred overnight to add (S)-ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl).Crude product is cooled to 0 ℃, drips water, evaporate with pH regulator to 7 and with mixture.Add DCM and several methyl alcohol and crude product is used 1M Na 2CO 3And water washing.Yield 58.6%. 1H-NMR(400MHz；DMSO-d6)：δ1.12(d，3H)，4.31(dd，1H)，4.40(dd，1H)，4.43-4.51(m，1H)，4.79(d，2H)，6.20(t，1H)，6.95(d，1H)，7.84(d，1H)，7.96(dd，1H)，7.98(dd，1H)，8.08(dd，1H)，8.13(s，1H)，8.50(d，1H)。
Embodiment 153
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
(S)-method that 2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-bromo-1; 3-thiazole-4-formic acid (0.6g; 2.88mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.627g 2.403mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 65.5%. 1H-NMR(400MHz；DMSO-d6)：δ1.12(d，3H)，4.23(dd，1H)，4.39(dd，1H)，4.42-4.50(m，1H)，6.96(d，1H)，7.84(d，1H)，8.00-8.01(m，2H)，8.07(dd，1H)，8.23(s，1H)，8.64(d，1H)。
Embodiment 154
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(methylamino) thiazole-4-carboxamide
(R)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(methylamino) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-(methylamino) thiazole-4-formic acid (0.34g; 2.149mmol) and (R)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.467g 1.791mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.Yield 9.08%. 1H-NMR(400MHz；DMSO-d6)：δ1.12(d，3H)，2.85(d，3H)，4.30-4.42(m，3H)，6.96(d，1H)，7.18(d，1H)，7.59(d，1H)，7.84(d，1H)，7.91(d，1H)，7.95-7.96(m，2H)，8.08(dd，1H)。
Embodiment 155
(S)-2-amino-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001381
azoles-4-methane amide
(S)-method that 2-amino-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001382
azoles-4-methane amide utilizes embodiment 34 (d) is with 2-amino-1; 3-
Figure BDA0000157427790001383
azoles-4-formic acid (0.196g; 1.527mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.437g 1.272mmol) prepares as raw material 2-chloro-3-methyl benzonitrile.Product is passed through purification by flash chromatography.Yield 29.0%. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，2.58(s，3H)，4.29(dd，1H)，4.39(dd，1H)，4.54(m，1H)，4.59(s，2H)，6.44(d，1H)，7.31(d，1H)，7.50(d，1H)，7.53(dd，1H)，7.58(dd，1H)，7.68(s，1H)。
Embodiment 156
(S)-2-amino-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
(S)-method that 2-amino-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with thiazolamine-4-formic acid (0.504g; 3.49mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.8g 2.91mmol) prepares as raw material 2-chloro-3-methyl benzonitrile.Product is passed through purification by flash chromatography.Yield 16.65%. 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，2.58(s，3H)，4.30(dd，1H)，4.40(dd，1H)，4.53(m，1H)，4.86(s，2H)，7.44(d，1H)，7.35(s，1H)，7.51(d，1H)，7.54(dd，1H)，7.57(d，1H)，7.63(d，1H)。
Embodiment 157
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-(methyl sulphonyl) piperidin-4-yl) thiazole-4-carboxamide
(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-(80mg 0.176mmol) joins in the flask under nitrogen atmosphere 2-(piperidin-4-yl) thiazole-4-carboxamide with (R)-N-.(20.14mg 0.176mmol) adds the exsiccant pyrido with the mixture stirred overnight together with methylsulfonyl chloride.Through adding the entry termination reaction.With reaction mixture with DCM dilution and use 1M Na 2CO 3And water washing.Product is developed with diethyl ether.Yield 35.5%. 1H-NMR(400MHz；CDCl 3)：δ1.29(d，3H)，1.92(m，2H)，2.18(m，2H)，2.81(dd，1H)，2.84(s，3H)，3.08(m，1H)，3.89(m，2H)，4.34(dd，1H)，4.42(dd，1H)，4.59(m，1H)，6.63(d，1H)，7.50(d，1H)，7.67(d，1H)，7.68(d，1H)，7.77(dd，1H)，7.98(d，1H)，8.01(s，1H)。
Embodiment 158
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(the 2-methoxy ethyl is amino) thiazole-4-carboxamide
(0.2g 0.444mmol) joins in the microwave bottle under nitrogen with the exsiccant pyridine with (S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide.(0.193ml 2.219mmol) and with mixture heated 10 hours down at 120 ℃ with microwave to add 2-methoxy ethyl amine.After this add 0.232ml 2-methoxy ethyl amine altogether and mixture is continued heating 10 hours.Product is passed through purification by flash chromatography.Yield 47.8%. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，3.41(s，3H)，3.44(m，2H)，3.57(m，2H)，4.29(dd，1H)，4.40(dd，1H)，4.54(m，1H)，5.39(t，1H)，6.62(d，1H)，7.33(d，1H)，7.49(d，1H)，7.68(dd，1H)，7.69(d，1H)，7.83(dd，1H)，7.98(dd，1H)。
Embodiment 159
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(pyridin-4-yl)-1H-pyrazole-3-formamide
Title compound according to the described method of embodiment 34 (d) with 1-(pyridin-4-yl)-1H-pyrazoles-3-formic acid (47.5mg; 0.251mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(70mg 0.251mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.The throw out that forms in the reaction process is leached from reaction mixture, with 2x 5ml water washing and 40 ℃ of following vacuum-dryings.Yield 73.7%. 1H-NMR(400MHz；DMSO-d6)：δ1.18(d，3H)，4.31-4.42(m，2H)，4.43-4.54(m，1H)，6.90(d，1H)，7.01(dd，1H)，7.79-8.01(m，5H)，8.39(d，1H)，8.66-8.73(m，2H)，8.77(d，1H)。
Embodiment 160
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
(S)-method that 2-bromo-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-bromo-1; 3-thiazole-4-formic acid (0.909g; 4.37mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(1g 3.64mmol) prepares as raw material 2-chloro-3-methyl benzonitrile.Product is passed through purification by flash chromatography.Yield 45.0%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，2.61(s，3H)，4.29(dd，1H)，4.45(dd，1H)，4.60(m，1H)，6.46(d，1H)，7.51(d，1H)，7.57(dd，1H)，7.61(dd，1H)，7.98(d，1H)，8.04(s，1H)。
Embodiment 161
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-((dimethylamino) methyl) thiazole-4-carboxamide
A) 2-((dimethylamino) methyl) thiazole-4-ethyl formate
With 2-chloromethyl-thiazole-4-ethyl formate (500mg, 2.431mmol) and salt of wormwood (504mg 3.65mmol) is dissolved in exsiccant DMF.(218mg, exsiccant DMF solution 2.67mmol) slowly join in the reaction mixture and at room temperature stir 3 evenings with the dimethyl amine hydrochloride.Add DCM and mixture is used dense NaHCO 3And water washing.Organic phase is evaporated to dry doubling product is passed through purification by flash chromatography.Yield 34.2%. 1H-NMR(400MHz；CDCl 3)：δ1.41(t，3H)，2.49(s，6H)，3.99(s，2H)4.43(q，2H)，8.20(s，1H)。
B) 2-((dimethylamino) methyl) thiazole-4-formic acid
With 2-((dimethylamino) methyl) thiazole-4-ethyl formate (147mg, 0.686mmol) be dissolved in THF/ carbinol mixture (9: 1) and slowly add the 1M Lithium Hydroxide MonoHydrate (1.372ml, 1.372mmol).Reaction mixture was at room temperature stirred 3 hours, be evaporated to the dried crude product that obtains title compound with pH regulator to 2 and with mixture.m/z[186.2+1]。
C) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-((dimethylamino) methyl) thiazole-4-carboxamide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-((dimethylamino) methyl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.149g; 0.573mmol) and 2-((dimethylamino) methyl) (128mg 0.687mmol) prepares as raw material thiazole-4-formic acid.Product is passed through purification by flash chromatography.Yield 0.814%. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，2.37(s，6H)，3.76(d，2H)，4.32(dd，1H)，4.42(dd，1H)，4.59(m，1H)，6.62(d，1H)，7.50(d，1H)，7.67(dd，1H)，7.81(dd，1H)，7.90(d，1H)，7.99(dd，1H)，8.06(s.1H)。
Embodiment 162
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-(methyl sulphonyl) piperidin-4-yl)
Figure BDA0000157427790001411
azoles-4-methane amide
A) 2-(1-(methyl sulphonyl) piperidin-4-yl)
Figure BDA0000157427790001412
azoles-4-ethyl formate
With 2-(4-piperidyl)-1; 3-
Figure BDA0000157427790001413
azoles-4-ethyl formate (500mg; 2.230mmol) and triethylamine (0.466ml 3.34mmol) is dissolved in exsiccant DCM and be cooled to 0 ℃.(0.190ml is 2.453mmol) and with reaction mixture stirred overnight at room temperature to add down slowly methylsulfonyl chloride at 0 ℃.Add less water carefully and organic phase is used 1M Na 2CO 3And water washing.The dry also evaporation of organic phase is obtained title compound (89%). 1H-NMR(400MHz；CDCl 3)：δ1.38(t，3H)，1.97-2.11(m，2H)，2.15-2.24(m，2H)，2.81(s，3H)，2.88-3.07(m，3H)，3.72-3.82(m，2H)，4.39(q，2H)，8.17(s，1H)。
B) 2-(1-(methyl sulphonyl) piperidin-4-yl)
Figure BDA0000157427790001414
azoles-4-formic acid
With 2-(1-(methyl sulphonyl) piperidin-4-yl)
Figure BDA0000157427790001415
azoles-4-ethyl formate (590mg; 1.951mmol) be dissolved in THF/ carbinol mixture (9: 1) and slowly add the 1M Lithium Hydroxide MonoHydrate (3.90ml, 3.90mmol).Reaction mixture was at room temperature stirred 1 hour dilute with water and with pH regulator to 1.5.With mixture with ethyl acetate extraction three times.ETHYLE ACETATE merged mutually and evaporate obtain title compound (74.7%). 1H-NMR(400MHz；DMSO)：δ1.68-1.81(m，2H)，2.06-2.15(m，2H)，2.85-2.96(m，5H)，2.99-3.10(m，1H)，3.51-3.59(m，2H)，8.67(s，1H)，13.02(bs，1H)。
C) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-(methyl sulphonyl) piperidin-4-yl)
Figure BDA0000157427790001421
azoles-4-methane amide
(S)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-(methyl sulphonyl) piperidin-4-yl)
Figure BDA0000157427790001422
azoles-4-methane amide utilizes embodiment 34 (d) is with 2-(1-(methyl sulphonyl) piperidin-4-yl) azoles-4-formic acid (0.4g; 01.458mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.317g 01.215mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through with the DCM extraction, with 0.1M HCl, 1M Na 2CO 3, water and brine wash and purifying.Yield 87%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，1.97(m，2H)，2.15(m，2H)，2.83(s，3H)，2.89(m，3H)，3.81(m，2H)，4.30(dd，1H)，4.41(dd，1H)，4.57(m，1H)，6.63(d，1H)，7.46(d，1H)，7.49(d，1H)，7.68(dd，1H)，7.79(dd，1H)，8.01(dd，1H)，8.11(s，1H)。
Embodiment 163
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(2-fluoro ethyl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-(130mg 0.269mmol) is suspended among the THF (5ml) 2-methyl isophthalic acid H-imidazoles-4-methane amide with (S)-N-.(123mg, 0.376mmol) (0.066ml is 0.807mmol) and with the mixture that forms stirred overnight at room temperature with 1-iodo-2-fluoroethane to add cesium carbonate.Added 0.2ml1-iodo-2-fluoroethane in second day and it's weekend is past mixture reaction.Add 1ml water and reaction mixture is evaporated.With the LC purifying of product with the MS triggering.Yield 27.5%. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，2.46(s，3H)，4.13-4.24(m，2H)，4.29(dd，1H)，4.40(dd，1H)，4.52-4.62(m，1H)，4.59-4.74(m，2H)，6.59(d，1H)，7.50-7.54(m，2H)，7.69(d，1H)，7.73-7.75(m，1H)，7.78(bs，1H)。
Embodiment 164
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(hydroxymethyl) thiazole-4-carboxamide
A) (S)-ethyl 4-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate
(S)-method that ethyl 4-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (400mg; 1.165mmol) and 2; (234mg 1.165mmol) prepares as raw material 4-thiazole dioctyl phthalate 2-ethyl ester.Product is passed through purification by flash chromatography.Yield 16.1%. 1H-NMR(400MHz；CDCl 3)：δ1.31(d，3H)，1.44(t，3H)，2.55(s，3H)，4.31-4-46(m，2H)，4.50(q，2H)，4.56-4.68(m，1H)，6.42(d，1H)，7.50(d，1H)，7.54-7.61(m，2H)，7.80(bd，1H)，8.34(s，1H)。
C) (S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(hydroxymethyl) thiazole-4-carboxamide
(14.21mg 0.376mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.(86mg 0.188mmol) and with reaction mixture slowly is warming up to room temperature to thiazole-2-manthanoate, simultaneously stirred overnight to add (S)-ethyl 4-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl).Crude product is cooled to 0 ℃, evaporates with pH regulator to 7 and with mixture.Add DCM and several methyl alcohol and crude product is used 1M Na 2CO 3And water washing.Yield 89%. 1H-NMR(400MHz；DMSO-d6)：δ1.13(d，3H)，2.53(s，3H)，4.23(dd，1H)，4.40(dd，1H)，4.49(m，1H)，4.75(d，2H)，6.21(t，1H)，6.62(d，1H)，7.64(dd，1H)，7.82(dd，1H)，7.85(d，1H)，8.13(s，1H)，8.43(d，1H)。
Embodiment 165
(S)-and N4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-N2, N2-dimethylthiazole-2,4-diformamide
(S)-N4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-N2; N2-dimethylthiazole-2; The 4-diformamide utilizes the method for embodiment 34 (d) with (S)-4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-formic acid (0.2g; 0.428mmol) and the dimethyl amine hydrochloride (0.029g 0.357mmol) prepares as raw material.Product is passed through purification by flash chromatography.Yield 23.42%. 1H-NMR(400MHz；DMSO-d6)：δ1.18(d，3H)，3.05(s，3H)，3.45(s，3H)，4.37(m，2H)，4.46(m，1H)，6.94(d，1H)，7.84(d，1H)，7.89(dd，1H)，7.95(d，1H)，8.04(d，1H)，8.30(d，1H)，8.43(s，1H)。
Embodiment 166
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(dimethylamino) thiazole-4-carboxamide
(0.247g 0.531mmol) joins in the microwave test tube with dry pyridine thiazole-4-carboxamide with (S)-2-bromo-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl).With mixture with nitrogen bubble and add the 2M dimethyl amine THF solution (1.329ml, 2.66mmol).Reaction mixture was heated 10 hours down at 120 ℃ with microwave.With the crude product evaporation,, use 1M Na with the DCM dilution 2CO 3And water washing.Product is used purification by flash chromatography.Yield 63.2%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，2.53(s，3H)，3.00(s，6H)，4.32(dd，1H)，4.41(dd，1H)，4.55(m，1H)，6.41(d，1H)，7.30(d，1H)，7.52(m，3H)，7.74(d，1H)。
Embodiment 167
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(trifluoromethyl) thiazole-4-carboxamide
A) 2-(trifluoromethyl) thiazole-4-formic acid
With 2-(trifluoromethyl) thiazole-4-ethyl formate (400mg, 1.176mmol) be dissolved in THF/ carbinol mixture (9: 1) and slowly add the 1M Lithium Hydroxide MonoHydrate (3.55ml, 3.55mmol).Reaction mixture was at room temperature stirred 1 hour, with pH regulator to 2 and with reaction mixture with ethyl acetate extraction three times.ETHYLE ACETATE is merged mutually, and drying also is evaporated to dried.Yield 93%.m/z[197.1+1]
B) (S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(trifluoromethyl) thiazole-4-carboxamide
(S)-method that N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(trifluoromethyl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (376mg; 1.370mmol) and 2-(trifluoromethyl) thiazole-(324mg 1.644mmol) prepares as raw material 4-formic acid.Product is developed with DCM and heptane.Yield 13.35%. 1H-NMR(400MHz；CDCl 3)：δ1.27(d，3H)，2.57(s，3H)，4.31(dd，1H)，4.46(dd，1H)，4.65(m，1H)，4.45(d，1H)，7.51(d，1H)，7.53(d，1H)，7.57(d，1H)，8.03(d，1H)，8.33(s，1H)。
Embodiment 168
Acetate 1-(4-((S)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) ethyl ester
With N-((S)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide (0.1g, 0.233mmol) and DMAP (2.87mg 0.023mmol) joins in the flask under nitrogen.Add pyridine, with mixture be cooled to 0 ℃ and drip diacetyl oxide (0.023ml, 0.244mmol).Mixture slowly is heated to room temperature and stirring.2.5 after hour mixture is evaporated.Product is used purification by flash chromatography.Yield 80%. 1H-NMR(400MHz；CDCl 3)：δ1.27(d，3H)，1.59(dd，3H)，2.15(d，3H)，2.56(d，3H)，4.33(dd，1H)，4.43(dd，1H)，4.60(m，1H)，6.03-6.11(m，1H)，6.43(d，1H)，7.50-7.58(m，3H)，7.77-7.88(m，1H)，8.05(s，1H)。
Embodiment 169
(S)-2-((1H-imidazoles-1-yl) methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001451
azoles-4-methane amide
A) 2-(chloromethyl)
Figure BDA0000157427790001452
azoles-4-formic acid
With 2-(chloromethyl)-1; 3-
Figure BDA0000157427790001453
azoles-4-methyl-formiate (1.0g; 5.70mmol) be dissolved in THF/ carbinol mixture (9: 1) and slowly add the 1M Lithium Hydroxide MonoHydrate (11.39ml, 11.39mmol).Reaction mixture was at room temperature stirred 1 hour dilute with water and with pH regulator to 2.With reaction mixture with ethyl acetate extraction three times.ETHYLE ACETATE is merged mutually, and drying also is evaporated to the dried title compound (94%) that obtains. 1H-NMR(400MHz；DMSO 3)：δ4.93(s，2H)，8.80(s，1H)，13.20(bs，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(chloromethyl)
Figure BDA0000157427790001461
azoles-4-methane amide
With 2-(chloromethyl)
Figure BDA0000157427790001462
azoles-4-formic acid (400mg; 2.476mmol) and 1; (5110mg 2.476mmol) is dissolved in exsiccant DCM and stirring 30 minutes to 3-DCC.(646mg, exsiccant DCM solution 2.476mmol) join in the reaction mixture and stirred overnight at room temperature with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Reaction mixture is diluted and the water washed twice with DCM.Organic phase is evaporated to dry doubling product is used purification by flash chromatography.Yield 36.9%.m/z[404.3+1]。
C) (S)-2-((1H-imidazoles-1-yl) methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001463
azoles-4-methane amide
(11.87mg 0.297mmol) joins in the flask under nitrogen atmosphere with sodium hydride.Flask is cooled to 0 ℃ also adds DMF through barrier film.(13.47mg 0.198mmol) and with mixture at room temperature stirred 60 minutes to add imidazoles.Mixture is cooled to 0 ℃ and dropping (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(chloromethyl)
Figure BDA0000157427790001464
azoles-4-methane amide (80mg, DMF solution 0.198mmol) once more.With reaction mixture stirred overnight at room temperature.Be dissolved in DCM with the DMF evaporation and with the crude product that forms, with brine wash and evaporation.With product with diethyl ether development and pass through purification by flash chromatography.Yield 8.23%. 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，4.29(dd，1H)，4.41(dd，1H)，4.58(m，1H)，5.26(s，2H)，6.64(d，1H)，7.00(t，1H)，7.11(t，1H)，7.49(d，1H)，7.60(s，1H)，7.61(d，1H)，7.68(d，1H)，7.78(dd，1H)，8.08(d，1H)，8.17(s，1H)。
Embodiment 170
(S)-and N4-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-N2, N2-dimethylthiazole-2,4-diformamide
(S)-N4-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-N2; N2-dimethylthiazole-2; The 4-diformamide utilizes the method for embodiment 34 (d) with (S)-4-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-formic acid (0.2g; 0.340mmol) and the dimethyl amine hydrochloride (0.023g 0.283mmol) prepares as raw material.Product is developed through purification by flash chromatography and with diethyl ether respectively.Yield 4.18%. 1H-NMR(400MHz；CDCl 3)：δ1.27(d，3H)，2.51(s，3H)，3.09(s，3H)，3.24(s，3H)，4.23(dd，1H)，4.45(dd，1H)，4.62(m，1H)，6.41(d，1H)，7.48(d，1H)，7.51(d，1H)，7.54(dd，1H)，7.85(d，1H)，8.27(s，1H)。
Embodiment 171
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(2-hydroxy propane-2-yl) thiazole-4-carboxamide
A) (S)-ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate
(S)-method that ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazole-2-manthanoate utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (540mg; 2.071mmol) and 2; (500mg 2.485mmol) prepares as raw material 4-thiazole dioctyl phthalate 2-ethyl ester.Yield 82%. 1H-NMR(400MHz；DMSO 3)：δ1.18(d，3H)，1.35(t，3H)，4.35(dd，1H)，4.39-4.57(m，4H)，6.94(d，1H)，7.84(d，1H)，7.95(m，2H)，8.02(m，1H)，8.55(s，1H)，8.61(d，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(2-hydroxy propane-2-yl) thiazole-4-carboxamide
(0.755g 1.701mmol) is dissolved in exsiccant THF to thiazole-2-manthanoate under nitrogen with (S)-ethyl 4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl).Solution is cooled to-78 ℃ with acetone-the dry ice bath.The Et that adds the 3M methyl-magnesium-bromide 2(1.134ml 3.40mmol) and with reaction mixture at room temperature stirs O solution.Reaction finishes the back and adds saturated ammonium chloride, water and DCM.Organic phase is used water washing.Product is used purification by flash chromatography.Yield 4.24%. 1H-NMR(400MHz；CDCl 3)：δ1.28(d，3H)，1.65(d，6H)，3.00(s，1H)，4.35(dd，1H)，4.42(dd，1H)，4.58(m，1H)，6.62(d，1H)，7.50(d，1H)，7.66(d，1H)，7.67(d，1H)，7.80(dd，1H)，7.91(d，1H)，8.00(s，1H)。
Embodiment 172
(R)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) butane-2-yl)
Figure BDA0000157427790001481
azoles-4-methane amide
(R)-method that N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) butane-2-yl)
Figure BDA0000157427790001482
azoles-4-methane amide utilizes embodiment 34 (d) is with 4-
Figure BDA0000157427790001483
iminazole acid (0.2g; 1.769mmol) and (R)-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-(0.532g 1.474mmol) prepares as raw material 2-chloro-3-methyl benzonitrile 4-.Product is developed with diethyl ether.Yield 29.9%. 1H-NMR(400MHz；CDCl 3)：δ1.02(t，3H)，1.58(m，2H)，2.57(s，3H)，4.39(m，3H)，6.43(d，1H)，7.45(d，1H)，7.49(d，1H)，7.53(dd，1H)，7.58(d，1H)，7.85(d，1H)，8.22(d，1H)。
Embodiment 173
(S)-(4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) methyl 2-(dimethylamino) acetic ester
(S)-(4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) methyl 2-(dimethylamino) acetic ester utilizes the method for embodiment 34 (d) to use N; N-N-methylsarcosine (0.062g; 0.597mmol) and (S)-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-(0.2g 0.498mmol) prepares as raw material 2-(hydroxymethyl) thiazole-4-carboxamide N-.With product with diethyl ether development and pass through purification by flash chromatography.Yield 39.5%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，2.39(s，6H)，3.30(s，2H)，4.31(dd，1H)，4.43(dd，1H)，4.60(m，1H)，5.43(d，2H)，6.63(d，1H)，7.49(d，1H)，7.70(d，1H)，7.84(dd，1H)，7.95(d，1H)，7.97(d，1H)，8.12(s，1H)。
Embodiment 174
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-pyrazole-3-yl) thiazole-4-carboxamide
A) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) thiazole-4-carboxamide
In the microwave flask, add (S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide (300mg; 0.666mmol), 1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-boric acid pinacol ester (222mg; 0.799mmol), tetrakis triphenylphosphine palladium (23mg, 0.020mmol), THF and 2M Na 2CO 3Solution also heated 2 hours down at 120 ℃ in microwave.Add 1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-boric acid pinacol ester (37mg) and tetrakis triphenylphosphine palladium (8mg) and reaction mixture is descended heating 1 hour at 120 ℃.With reaction mixture with DCM dilution and use Na 2CO 3Twice of solution washing.Organic phase is dry and be evaporated to dried.Product is passed through purification by flash chromatography.Yield 3.7%.m/z[522.0+1]。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-pyrazole-3-yl) thiazole-4-carboxamide
((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-(13mg 0.025mmol) joins in the flask under nitrogen atmosphere thiazole-4-carboxamide 2-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) with N-.(0.028ml 0.062mmol) and with reaction mixture at room temperature stirred 3 hours to add 10%HCl/EtOH.With reaction mixture with ETHYLE ACETATE dilution and use 1M Na 2CO 3Washing.Organic phase is dry, filter and evaporation.Yield 94%. 1H-NMR(400MHz；MeOD)：δ1.30(d，3H)，4.38(dd，1H)，4.45(dd，1H)，4.59(m，1H)，6.75(d，1H)，6.83(d，1H)，7.61(d，1H)，7.73(d，1H)，7.76(d，1H)，7.84(dd，1H)，7.95(d，1H)，8.06(s，1H)。
Embodiment 175
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1H-imidazol-4 yl)-1; 2,4-
Figure BDA0000157427790001501
diazole-5-methane amide
A) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-trityl-1H-imidazol-4 yl)-1; 2,4-
Figure BDA0000157427790001502
diazole-5-methane amide
To containing 3-(1-trityl-1H-imidazol-4 yl)-1; 2; (0.148g is 0.350mmol) with anhydrous HOBt (0.047g for 4-
Figure BDA0000157427790001503
diazole-5-formic acid; 0.350mmol) flask in add methylene dichloride (2ml), DIPEA (0.122ml; 0.700mmol) and EDCI (0.067g; 0.350mmol) and at room temperature stirred 10 minutes.(0.100g is 0.269mmol) and with the mixture stirred overnight that forms to add (S)-4-(1-(2-aminopropyl)-1H-the pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile be dissolved in the 2ml methylene dichloride.Temperature risen to 50 ℃ and add EDCI (0.067g in second day; 0.350mmol).Reaction mixture was under agitation reacted 4 hours.Add DCM and organic layer is used 1M Na 2CO 3Extract with water.Use purification by flash chromatography with the organic layer evaporation and with resistates then.LC-MS：[M+1]＝684.133。
B) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1H-imidazol-4 yl)-1; 2,4- diazole-5-methane amide
To containing (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-trityl-1H-imidazol-4 yl)-1; 2; 4-
Figure BDA0000157427790001505
diazole-5-methane amide (0.073g; 0.107mmol) flask in; Add contain THF (9ml), formic acid (2.459ml, 53.4mmol) and the mixture of water (0.1ml).The mixture that forms was at room temperature stirred 24 hours.Evaporating solvent.Add acetonitrile (15ml) and evaporation.Repeat them more than 3 times.With the LC purifying of product with the MS triggering.Yield 46.3%. 1H-NMR(400MHz；DMSO-d6)：δ1.21(d，3H)，4.32-4.40(m，2H)，4.42-4.54(m，1H)，7.02(d，1H)，7.81-7.92(m，4H)，7.94(s，1H)，9.43(d，1H)，12.69(s，1H)。
Embodiment 176
N-((R)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) butane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide
A) (R)-4-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile
(R)-4-(1-(2-amino butyl)-1H-pyrazole-3-yl)-method that 2-chloro-3-methyl benzonitrile utilizes embodiment 99 is with 2-chloro-3-methyl-4-(1H-pyrazole-3-yl) benzonitrile (2.0g; 9.19mmol) and (R)-tertiary butyl 1-hydroxyl butane-(3.48g 18.38mmol) prepares as raw material 2-aminocarbamic acid ester.Yield 56.5%.m/z[288.8+1]。
B) (R)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) butane-2-yl) thiazole-4-carboxamide
(R)-method that 2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) butane-2-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with (R)-4-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (489mg; 1.355mmol) and 2-acetylthiazole-4-formic acid (278mg 1.626mmol) prepares as raw material.Product is passed through purification by flash chromatography.Yield 11.4%. 1H-NMR(400MHz；CDCl 3)：δ1.05(t，3H)，1.56-1.67(m，2H)，2.53(s，3H)，2.53(s，3H)，4.36-4.52(m，3H)，6.42(d，1H)，7.47-7.55(m，3H)，7.88(d，1H)，8.39(s，1H)。
C) N-((R)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) butane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide
(7.19mg 0.190mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.(42mg 0.095mmol) and with reaction mixture slowly is warming up to room temperature, simultaneously stirred overnight to add (R)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) butane-2-yl) thiazole-4-carboxamide.Crude product is cooled to 0 ℃, with pH regulator to being about 3 and mixture evaporated.Add 5%DCM/MeOH and crude product is used 1M NaHCO 3, water washing and dry.Yield 74.2%. 1H-NMR (400MHz; CDCl 3): δ 1.03 (m, 3H), 1.56-1.59 (m, 3H), 2.54&2.55 (s that 2x is wide, 3H), 4.34-4.46 (m, 3H), 5.07 (dd, 1H), 6.41-6.43 (m, 1H), 7.46-7.54 (m, 3H), 7.80-7.89 (m, 1H), 8.02 (s, 1H).
Embodiment 177
N-((S)-2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-5-(1-hydroxyethyl) different
Figure BDA0000157427790001521
azoles-3-methane amide
A) 5-ethanoyl different
Figure BDA0000157427790001522
azoles-3-formic acid
With 5-ethanoyl different
Figure BDA0000157427790001523
azoles-3-ethyl formate (300mg; 1.638mmol) be dissolved in THF/ carbinol mixture (9: 1) and slowly add the 1M Lithium Hydroxide MonoHydrate (3.28ml, 3.28mmo1).Reaction mixture was at room temperature stirred 40 minutes dilute with water and with pH regulator to 3.With reaction mixture with ethyl acetate extraction three times.ETHYLE ACETATE is merged mutually, use brine wash, drying also is evaporated to the dried title compound (29.9%) that obtains.m/z[155.1+1]。
B) (S)-5-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group) different
Figure BDA0000157427790001524
azoles-3-methane amide
(S)-method that 5-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group) different
Figure BDA0000157427790001525
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (106mg; 0.408mmol) and 5-ethanoyl different
Figure BDA0000157427790001526
(76mg 0.490mmol) prepares as raw material azoles-3-formic acid.Product is passed through purification by flash chromatography.Yield 24.6%. 1H-NMR(400MHz；CDCl 3)：δ1.63(d，3H)，2.63(s，3H)，3.78-3.88(m，1H)，3.91-4.00(m，1H)，4.59-4.69(m，1H)，6.63(d，1H)，7.29(s，1H)，7.50(s，1H)，7.67-7.77(m，2H)，7.82(dd，1H)，8.05(d，1H)。
C) N-((S)-2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-5-(1-hydroxyethyl) different azoles-3-methane amide
(6.41mg 0.169mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.Add (S)-5-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group) different azoles-3-methane amide (33.7mg; 0.085mmol) and reaction mixture slowly is warming up to room temperature, stirred overnight simultaneously.Crude product is cooled to 0 ℃, with pH regulator to being about 3 and mixture evaporated.Add 5%DCM/MeOH and crude product is used 1M NaHCO 3, water washing and dry.Yield 96%. 1H-NMR(400MHz；CDCl 3)：δ1.57-1.65(m，3H)3.75-3.84(m，1H)，3.87-3.95(m，1H)，4.57-4.67(m，1H)，5.03(q，1H)，6.61(d，1H)，6.62(s，1H)，7.50(d，1H)，7.56-7.63(m，1H)，7.65-7.69(2x?s，1H)，7.81(dd，1H)，8.01(d，1H)。
Embodiment 178
(S)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) azoles-4-methane amide
(S)-method that 2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001532
azoles-4-methane amide utilizes embodiment 34 (d) is with 2-ethanoyl
Figure BDA0000157427790001533
azoles-4-formic acid (372mg; 2.400mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(549mg 2.000mmol) prepares as raw material 2-chloro-3-methyl benzonitrile.With product with diethyl ether development and pass through purification by flash chromatography.Yield 12.47%. 1H-NMR(400MHz；CDCl 3)：δ1.27(d，3H)，2.59(s，3H)，2.60(s，3H)，4.31(dd，1H)，4.45(dd，1H)，4.64(m，1H)，6.45(d，1H)，7.51(d，1H)，7.56(m，2H)，7.68(d，1H)，8.31(s，1H)。
Embodiment 179
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) pyridine-2-carboxamide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) pyridine-2-carboxamide utilizes embodiment 34 (d) is with VPP (0.227g; 1.841mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.534mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Yield 73.7%. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，4.31(dd，1H)，4.45(dd，1H)，4.62(m，1H)，6.63(d，1H)，7.46(m，1H)，7.50(d，1H)，7.67(d，1H)，7.81(dd，1H)，7.86(m，1H)，8.09(d，1H)，8.19(m，1H)，8.65(m，1H)，8.86(d，1H)。
Embodiment 180
N-((S)-2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-2-(1-hydroxyethyl)
Figure BDA0000157427790001541
azoles-4-methane amide
A) (S)-2-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)
Figure BDA0000157427790001542
azoles-4-methane amide
(S)-method that 2-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)
Figure BDA0000157427790001543
azoles-4-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (521mg; 2.00mmol) and 2-ethanoyl
Figure BDA0000157427790001544
(372mg 2.40mmol) prepares as raw material azoles-4-formic acid.Product is passed through purification by flash chromatography.Yield 36.0%. 1H-NMR(400MHz；CDCl 3)：δ1.62(d，3H)，2.61(s，3H)，3.75-3.98(m，2H)，4.59-4.71(m，1H)，6.62(d，1H)，7.45-7.53(m，2H)，7.71(d，1H)，7.86(dd，1H)，7.98(d，1H)，8.32(s，1H)。
B) N-((S)-2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)-2-(1-hydroxyethyl)
Figure BDA0000157427790001545
azoles-4-methane amide
(0.051g 1.352mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.Add (S)-2-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group)
Figure BDA0000157427790001546
azoles-4-methane amide (0.269g; 0.676mmol) and reaction mixture slowly is warming up to room temperature, stirred overnight simultaneously.Crude product is cooled to 0 ℃, with evaporating below the pH regulator to 7 and with mixture.Add 5%DCM/MeOH and crude product is used 1M NaHCO 3, water washing and dry.Yield 84%. 1H-NMR(400MHz；CDCl 3)：δ1.58(d，3H)，1.61(d，3H)，2.40(d，1H)，3.79(m，1H)，3.89(m，1H)，4.62(m，1H)，4.94(m，1H)，6.61(d，1H)，7.46(m，1H)，7.49(d，1H)，7.69(d，1H)，7.85(dd，1H)，7.98(d，1H)，8.15(s，1H)。
Embodiment 181
N-((S)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl)
Figure BDA0000157427790001547
azoles-4-methane amide
(0.037g 0.971mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.Add (S)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001551
azoles-4-methane amide (0.2g; 0.486mmol) and reaction mixture slowly is warming up to room temperature, stirred overnight simultaneously.Crude product is cooled to 0 ℃, with evaporating below the pH regulator to 7 and with mixture.Add 5%DCM/MeOH and crude product is used 1M NaHCO 3, water washing and dry.Product is used purification by flash chromatography.Yield 55.4%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，1.59(d，3H)，2.50(s，1H)，2.58(s，3H)，4.30(dd，1H)，4.42(dd，1H)，4.59(m，1H)，4.94(m，1H)，6.44(d，1H)，7.54(m，4H)，8.14(s，1H)。
Embodiment 182
(S)-2-(3-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) different
Figure BDA0000157427790001552
azoles-5-yl) propane-2-yl acetate
With (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790001553
azoles-3-methane amide (97mg; 0.234mmol) and DMAP (2.89mg 0.023mmol) is dissolved in pyridine under nitrogen.Reaction mixture is cooled to 0 ℃, and (25.1mg 0.246mmol) and with reaction mixture at room temperature stirred 2 hours to add diacetyl oxide.Mixture is cooled to 0 ℃ and add 10 μ l diacetyl oxides once more.With reaction mixture at room temperature stirred overnight, evaporating solvent then.Yield 99%. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，1.80(s，6H)，2.05(s，3H)，4.25(dd，1H)，4.42(dd，1H)，4.58(m，1H)，6.58(s，1H)，6.63(d，1H)，7.49(d，1H)，7.69(d，1H)，7.83(dd，1H)，7.89(d，1H)，8.09(d，1H)。
Embodiment 183
(S)-5-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) different azoles-3-methane amide
(S)-method that 5-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001555
azoles-3-methane amide utilizes embodiment 34 (d) is with 5-ethanoyl different
Figure BDA0000157427790001556
azoles-3-formic acid (0.200g; 1.292mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.3g 1.076mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through purification by flash chromatography.Yield 16.09%. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，2.65(s，3H)，4.26(dd，1H)，4.46(dd，1H)，4.61(m，1H)，6.64(d，1H)，7.29(s，1H)，7.51(d，1H)，7.63(dd，1H)，7.85(s，1H)，8.04(d，1H)。
Embodiment 184
N-((S)-1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different
Figure BDA0000157427790001561
azoles-3-methane amide
(0.012g 0.308mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.Add (S)-5-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001562
azoles-3-methane amide (0.064g; 0.154mmol) and reaction mixture slowly is warming up to room temperature, stirred overnight simultaneously.Crude product is cooled to 0 ℃, with evaporating below the pH regulator to 7 and with mixture.Add 5%DCM/MeOH and crude product is used 1M NaHCO 3, water washing and dry.Yield 81%. 1H-NMR(400MHz；DMSO-d6)：δ1.16(d，3H)，1.40(dd，3H)，4.32(d，2H)，4.45(m，1H)，4.86(m，1H)，5.78(dd，1H)，6.53(dd，1H)，7.00(d，1H)，7.84(d，1H)，7.86(m，1H)，7.98(d，1H)，8.75(d，1H)。
Embodiment 185
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-pyrazole-3-yl) azoles-4-methane amide
A) 2-bromine
Figure BDA0000157427790001564
azoles-4-formic acid
With 2-bromo-1; 3-
Figure BDA0000157427790001565
azoles-4-ethyl formate (2.5g; 11.36mmo) be dissolved in THF/ carbinol mixture (9: 1) and slowly add the 1M Lithium Hydroxide MonoHydrate (22.73ml, 22.73mmol).Reaction mixture was at room temperature stirred 1 hour dilute with water and with pH regulator to 2.Filtering the throw out that forms also, drying obtains title compound (1.1g).To filtrate with ethyl acetate extraction three times.ETHYLE ACETATE is merged mutually, and drying also is evaporated to the dried title compound 0.85g that obtains.Total recovery 88%.m/z[192.0+1]。
B) (S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) azoles-4-methane amide
(S)-method that 2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) azoles-4-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (741mg; 2.82mmol) and 2-bromine
Figure BDA0000157427790001573
(850mg 3.41mmol) prepares as raw material azoles-4-formic acid.Product is passed through purification by flash chromatography.Yield 12.4%. 1H-NMR(400MHz；CDCl 3)：δ1.20(d，3H)，4.18-4.47(m，2H)，4.51-4.65(m，1H)，6.64(d，1H)，7.48(d，1H)，7.72(dd，1H)，7.92-7.99(m，3H)，8.21(s，1H)。
C) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) azoles-4-methane amide
In the microwave flask, add (S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001575
Azoles-4-methane amide (153mg, 0.352mmol), 1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-boric acid pinacol ester (490mg, 1.760mmol), tetrakis triphenylphosphine palladium (4.07mg, 3.52umol), THF and 2M Na 2CO 3Solution also heated 1 hour under 100 ℃.With reaction mixture with DCM dilution and use NaHCO 3Twice of solution washing.Organic phase is dry and be evaporated to dried.Product is passed through purification by flash chromatography twice.Yield 31.4%.m/z[506.0+1]。
D) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-pyrazole-3-yl) azoles-4-methane amide
((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-(56mg 0.111mmol) joins in the flask under nitrogen atmosphere
Figure BDA0000157427790001577
azoles-4-methane amide 2-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) with N-.(0.126ml 0.277mmol) and with reaction mixture at room temperature stirred 2 hours to add 10%HCl/EtOH.With reaction mixture with ETHYLE ACETATE dilution and use 1M Na 2CO 3Washing.Organic phase is dry, filter and evaporation.Product is developed with acetonitrile and THF respectively.Yield 29.6%. 1H-NMR(400MHz；CDCl 3)：δ1.27(d，3H)，4.31(dd，1H)，4.43(dd，1H)，4.61(m，1H)，6.61(d，1H)，6.86(d，1H)，7.49(d，1H)，7.60(d，1H)，7.66(d，1H)，7.72(d，1H)，7.87(dd，1H)，7.92(d，1H)，8.23(s，1H)，10.78(s，1H)。
Embodiment 186
N-((S)-1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide
(0.056g 1.477mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.(0.316g 0.738mmol) and with reaction mixture slowly is warming up to room temperature, simultaneously stirred overnight to add (S)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide.Crude product is cooled to 0 ℃, adds several dripping, with evaporating below the pH regulator to 7 and with mixture.Add 5%DCM/MeOH and crude product is used 1M NaHCO 3, water washing and dry.Yield 68.1%. 1H-NMR(400MHz；DMSO-d6)：δ1.13(d，3H)，1.40(dd，3H)，2.52(s，3H)，4.37(m，2H)，4.48(m，1H)，4.92(m，1H)，6.24(t，1H)，6.62(d，1H)，7.63(d，1H)，7.82(d，1H)，7.87(dd，1H)，8.10(s，1H)，8.37(dd，1H)。
Embodiment 187
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-sec.-propyl-1-(3-sec.-propyl-1H-pyrazoles-5-carbonyl)-1H-pyrazoles-5-methane amide
(S)-the N-method that (1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-sec.-propyl-1-(3-sec.-propyl-1H-pyrazoles-5-carbonyl)-1H-pyrazoles-5-methane amide utilizes embodiment 34 (d) is with 3-sec.-propyl-1H-pyrazoles-5-formic acid (0.284g; 1.841mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.4g 1.534mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Yield 1.883%. 1H-NMR(400MHz；CDCl 3)：δ1.23(dd，6H)，1.27(d，3H)，1.32(dd，6H)，2.94(m，1H)，3.81(m，1H)，4.32(dd，1H)，4.47(dd，1H)，4.63(m，1H)，6.63(d，1H)，6.81(s，1H)，7.08(s，1H)，7.44(d，1H)，7.51(d，1H)，7.64(dd，1H)，7.78(d，1H)，7.80(d，1H)。
Embodiment 188
3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl)-1H-pyrazoles-5-methane amide
3-ethanoyl-N-method that (2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl)-1H-pyrazoles-5-methane amide utilizes embodiment 34 (d) is with 3-ethanoyl-1H-pyrazoles-5-formic acid (84mg; 0.542mmol) and 4-(1-(1-amino-3-hydroxy propane-2-yl)-1H-pyrazole-3-yl)-(125mg 0.452mmol) prepares as raw material 2-benzyl chloride nitrile.Product is developed with diethyl ether and acetonitrile respectively.Yield 6.49%. 1H-NMR(400MHz；MeOD)：δ2.51(s，3H)，3.88(m，2H)，3.97(dd，1H)，4.03(dd，1H)，4.65(m，1H)，6.77(d，1H)，7.21(s，1H)，7.75(d，1H)，7.79(d，1H)，7.91(dd，1H)，8.05(d，1H)。
Embodiment 189
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(the 2-methoxy ethyl is amino) thiazole-4-carboxamide
(0.2g 0.430mmol) joins in the microwave bottle with the dry pyridine as solvent thiazole-4-carboxamide with (S)-2-bromo-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl)-propane-2-yl) under nitrogen.(0.187ml 2.152mmol) and with mixture heats down at 120 ℃ with microwave to add 2-methoxy ethyl amine.Added altogether 0.187ml 2-methoxy ethyl amine in second day and reaction mixture is continued heating 3 hours.Be dissolved in DCM with the reaction mixture evaporation and with crude product, use Na 2CO 3, water and brine wash.Product is passed through purification by flash chromatography.Yield 38.5%. 1H-NMR(400MHz；MeOD)：δ1.25(d，3H)，2.50(s，3H)，3.35(s，3H)，3.40-3.43(m，2H)，3.46-3.49(m，2H)，4.34(dd，1H)，4.41(dd，1H)，4.47-4.56(m，1H)，6.49(d，1H)，7.19(s，1H)，7.55(d，1H)，7.64(dd，1H)，7.73(d，1H)。
Embodiment 190
N-((S)-2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propyl group)-2-(1-hydroxyethyl)
Figure BDA0000157427790001591
azoles-4-methane amide
A) (S)-2-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propyl group)
Figure BDA0000157427790001601
azoles-4-methane amide
(S)-method that 2-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propyl group)
Figure BDA0000157427790001602
azoles-4-methane amide utilizes embodiment 34 (d) is with ((S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (549mg; 2.00mmol) and 2-ethanoyl
Figure BDA0000157427790001603
(372mg 2.40mmol) prepares as raw material azoles-4-formic acid.Product is passed through purification by flash chromatography.Yield 33.4%. 1H-NMR(400MHz；CDCl 3)：δ1.63(d，3H)，2.58(d，3H)，2.60(s，3H)，3.78-3.98(m，2H)，4.60-4.71(m，1H)，6.44(d，1H)，7.44-7.62(m，4H)，8.31(s，1H)。
B) N-((S)-2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propyl group)-2-(1-hydroxyethyl)
Figure BDA0000157427790001604
azoles-4-methane amide
(0.055g 1.462mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.Add (S)-2-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propyl group) azoles-4-methane amide (0.301g; 0.731mmol) and reaction mixture slowly is warming up to room temperature, stirred overnight simultaneously.Crude product is cooled to 0 ℃, evaporates with pH regulator to 6 and with mixture.Add 5% methyl alcohol/DCM and crude product is used 1M NaHCO 3And water washing.Dry and the evaporation with mixture.Yield 94%. 1H-NMR(400MHz；CDCl 3)：δ1.57(d，3H)，1.61(d，3H)，3.78-3.83(m，1H)，3.87-3.94(m，1H)，4.59-4.68(m，1H)，4.87-4.96(m，1H)，6.43(d，1H)，7.34-7.42(m，1H)，7.51(d，1H)，7.54-7.61(m，2H)，8.14(s，1H)。
Embodiment 191
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(the 2-methoxy ethyl is amino)
Figure BDA0000157427790001606
azoles-4-methane amide
A) (S)-2-bromo-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001607
azoles-4-methane amide
(S)-method that 2-bromo-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001611
azoles-4-methane amide utilizes embodiment 34 (d) is with ((S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (742mg; 2.70mmol) and 2-bromine
Figure BDA0000157427790001612
(492mg 2.56mmol) prepares as raw material azoles-4-formic acid.Product is passed through purification by flash chromatography.Yield 6.2%.m/z[448.7+1]。
B) (S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(the 2-methoxy ethyl is amino)
Figure BDA0000157427790001613
azoles-4-methane amide
(0.180g 0.401mmol) joins in the microwave bottle with the dry pyridine as solvent
Figure BDA0000157427790001614
azoles-4-methane amide with (S)-2-bromo-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl).Mixture is used nitrogen bubble.(0.129ml 2.407mmol) and with mixture heated 2 hours down at 120 ℃ with microwave to add 2-methoxy ethyl amine.Product is passed through purification by flash chromatography.Yield 15.65%. 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，2.58(s，3H)，3.39(s，3H)，3.44(t，2H)，3.51(t，2H)，4.30(dd，1H)，4.40(dd，1H)，4.51-4.60(m，1H)，5.07(t，1H)，6.44(d，1H)，7.40(d，1H)，7.51(d，1H)，7.52-7.58(m，2H)，7.67(s，1H)。
Embodiment 192
(R)-5-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group) different azoles-3-methane amide
(R)-method that 5-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propyl group) different azoles-3-methane amide utilizes embodiment 34 (d) is with 5-ethanoyl different
Figure BDA0000157427790001617
azoles-3-formic acid (0.314g; 2.025mmol) and (R)-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-(0.44g 1.688mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.Yield 19.16%. 1H-NMR(400MHz；CDCl 3)：δ1.63(d，3H)，2.63(s，3H)，3.79-3.87(m，1H)，3.92-3.99(m，1H)，4.60-4.66(m，1H)，6.63(d，1H)，7.29(s，1H)，7.50(d，1H)，7.69-7.74(m，2H)，7.82(dd，1H)，8.05(d，1H)。
Embodiment 193
(S)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
(S)-method that 2-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide utilizes embodiment 34 (d) is with 2-acetylthiazole-4-formic acid (0.680g; 3.49mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.8g 2.91mmol) prepares as raw material 2-chloro-3-methyl benzonitrile.Product is passed through purification by flash chromatography.Yield 30.0%. 1H-NMR(400MHz；CDCl 3)：δ1.30(d，3H)，2.53(s，3H)，2.54(s，3H)，4.35(dd，1H)，4.47(dd，1H)，4.61-4.69(m，1H)，6.44(d，1H)，7.49-7.54(m，3H)，7.95(d，1H)，8.39(s，1H)。
Embodiment 194
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl) azoles-4-methane amide
(S)-method that 2-amino-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) butane-2-yl)
Figure BDA0000157427790001622
azoles-4-methane amide utilizes embodiment 34 (d) is with 2-amino-1; 3-
Figure BDA0000157427790001623
azoles-4-formic acid (343mg; 2.68mmol) and (S)-(1-(the amino butyl of 2-)-1H-pyrazole-3-yl)-(613mg 2.231mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed with diethyl ether.Yield 4.32%. 1H-NMR(400MHz；DMSO-d6)：δ0.86(t，3H)，1.41-1.51(m，2H)，4.18-4.39(m，3H)，6.78(s，2H)，6.93(d，1H)，7.74(d，1H)，7.76(s，1H)，7.79(d，1H)，7.94-8.00(m，2H)，8.08(s，1H)。
Embodiment 195
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-((2,5-dioxo tetramethyleneimine-1-yl) methyl)
Figure BDA0000157427790001624
azoles-4-methane amide
With (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(chloromethyl)
Figure BDA0000157427790001625
azoles-4-methane amide (0.132g; 0.327mmol) and salt of wormwood (0.068g 0.490mmol) is dissolved in exsiccant DMF under nitrogen.(0.036g 0.359mmol) and with mixture at room temperature stirred 4.5 hours to add succimide.Add DCM and organic phase is used water washing.Product with diethyl ether, DCM development, is passed through purification by flash chromatography at last.Yield 16.92%. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，2.83(s，4H)，4.29(dd，1H)，4.39(dd，1H)，4.51-4.59(m，1H)，4.83(s，2H)，6.63(d，1H)，7.47(d，1H)，7.52(d，1H)，7.74(d，1H)，7.87(dd，1H)，7.98(d，1H)，8.11(s，1H)。
Embodiment 196
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl)
Figure BDA0000157427790001631
azoles-4-methane amide
A) (S)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001632
azoles-4-methane amide
(S)-method that 2-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001633
azoles-4-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (600mg; 2.301mmol) and 2-ethanoyl
Figure BDA0000157427790001634
(428mg 2.76mmol) prepares as raw material azoles-4-formic acid.Product is passed through purification by flash chromatography.Yield 11.6%. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，2.68(s，3H)，4.26-4.33(m，1H)，4.40-4.47(m，1H)，4.55-4.68(m，1H)，6.63(d，1H)，7.49(d，1H)，7.67(d，1H)，7.72(d，1H)，7.88(dd，1H)，7.93(d，1H)，8.31(s，1H)。
B) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl)
Figure BDA0000157427790001635
azoles-4-methane amide
(0.019g 0.498mmol) joins in the flask and with atmosphere and replaces with nitrogen with Peng Qinghuana.Add exsiccant ethanol and reaction mixture is cooled to 0 ℃.Add (S)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)
Figure BDA0000157427790001636
azoles-4-methane amide (0.099g; 00.249mmol) and reaction mixture slowly is warming up to room temperature, stirred overnight simultaneously.Crude product is cooled to 0 ℃, evaporates with pH regulator to 6 and with mixture.Add 5%DCM/MeOH and crude product is used 1M NaHCO 3, water washing and dry.Yield 89%. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，1.63(d，3H)，2.51(s，1H)，4.25-4.31(m，1H)，4.41(dd，1H)，4.54-4.63(m，1H)，5.00(q，1H)，6.61(d，1H)，7.49(d，1H)，7.68(d，1H)，7.70(d，1H)，7.86-7.89(m，1H)，7.95-7.96(m，1H)，8.15(s，1H)。
Embodiment 197
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-((2,5-dioxo tetramethyleneimine-1-yl) methyl) different
Figure BDA0000157427790001641
azoles-3-methane amide
A) (S)-5-(brooethyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001642
azoles-3-methane amide
With 5-(brooethyl) different
Figure BDA0000157427790001643
azoles-3-formic acid (1.027g; 4.99mmol) and DCC (1.029g; 4.99mmol) under nitrogen, be dissolved in exsiccant DCM and add (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (1.0g, 3.84mmol).With mixture stirred overnight and throw out filtered at room temperature.With the filtrate water washing, drying also is evaporated to dried.Evaporation residue is obtained title compound through purification by flash chromatography.Yield 83%. 1H-NMR(400MHz；DMSO)：δ1.17(d，3H)，4.32(d，2H)，4.40-4.50(m，1H)，4.86(s，2H)，6.81(s，1H)，6.94(d，1H)，7.82(d，1H)，7.91(dd，1H)，7.97(dd，1H)，8.08(dd，1H)。8.85(d，1H)
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-((2,5-dioxo tetramethyleneimine-1-yl) methyl) different
Figure BDA0000157427790001644
azoles-3-methane amide
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-((2; 5-dioxo tetramethyleneimine-1-yl) methyl) different (262mg 0.584mmol) prepares as raw material azoles-3-methane amide different
Figure BDA0000157427790001645
azoles-3-methane amide method of utilizing embodiment 195 with (S)-5-(brooethyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl).Product is passed through purification by flash chromatography.Yield 89%. 1H-NMR(400MHz；MeOD)：δ1.26(d，3H)，2.57(s，4H)，4.28-4.43(m，2H)，4.52-4.63(m，1H)，4.85(s，2H)，6.63(s?vai?d，1H)，6.71(d，1H)，7.65(d，1H)，7.68(d，1H)，7.75(d，1H)，7.85(dd，1H)，8.06(d，1H)。
Embodiment 198
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(methylamino) thiazole-4-carboxamide
(S)-method that N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(methylamino) thiazole-4-carboxamide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (300mg; 1.092mmol) and 2-(methylamino) thiazole-(314mg 1.613mmol) prepares as raw material 4-formate hydrochlorate.Product is passed through purification by flash chromatography twice (positive and anti-phase).Yield 4.86%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，2.56(s，3H)，2.93(d，3H)，4.28-4.43(m，2H)，4.47-4.61(m，1H)，5.04-5.12(m，1H)，6.43(d，1H)，7.31(d，1H)，7.49-7.56(m，3H)，7.67(m，1H)。
Embodiment 199
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(morpholino methyl) different
Figure BDA0000157427790001651
azoles-3-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(morpholino methyl) different
Figure BDA0000157427790001652
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.690mmol) and 5-(morpholino methyl) different
Figure BDA0000157427790001653
azoles-(206mg 0.828mmol) prepares as raw material 3-formate hydrochlorate.With product through the anti-phase purification by flash chromatography.Yield 16.9%. 1H-NMR(400MHz；MeOD)：δ1.26(d，3H)，2.47-2.56(m，4H)，3.65-3.71(m，4H)，3.75(d，2H)，4.28-4.44(m，2H)，4.53-4.63(m，1H)，6.59(t，1H)，6.77(d，1H)，7.71(d，1H)，7.78(dd，1H)，7.88(dd，1H)，8.08(dd，1H)。
Embodiment 200
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-methyl isophthalic acid H-imidazoles-4-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-methyl isophthalic acid H-imidazoles-4-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-methyl benzonitrile (300mg; 1.092mmol) and 1-methyl isophthalic acid H-imidazoles-(207mg 1.638mmol) prepares as raw material 4-formic acid.Product is passed through purification by flash chromatography twice (positive and anti-phase).Yield 38.7%. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，2.56(s，3H)，3.74(s，3H)，4.30-4.43(m，2H)，4.49-4.61(m，1H)，6.41(d，1H)，7.35(d，1H)，7.39(d，1H)，7.49-7.56(m，3H)，7.60(d，1H)。
Embodiment 201
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-isopropyl azoles-3-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-isopropyl
Figure BDA0000157427790001662
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (150mg; 0.575mmol) and 5-isopropyl
Figure BDA0000157427790001663
(98mg 0.633mmol) prepares as raw material azoles-3-formic acid.Product is developed through purification by flash chromatography and with methyl alcohol.Yield 7.86%. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，1.33(d，6H)，3.06-3.19(m，1H)，4.26(dd，1H)，4.43(dd，1H)，4.52-4.64(m，1H)，6.40(d，1H)，6.63(d，1H)，7.49(d，1H)，7.69(d，1H)，7.80(d，1H)，7.84(dd，1H)，8.06(s，1H)。
Embodiment 202
(S)-5-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propyl group) different
Figure BDA0000157427790001664
azoles-3-methane amide
A) (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile
With 2-chloro-6-fluoro-4-(1H-pyrazole-3-yl) benzonitrile (5.0g, 22.56mmol), N-t-BOC-(R)-1-amino-2-propyl alcohol (7.91g, 45.1mmol) and triphenylphosphine (11.84g 45.1mmol) is dissolved in exsiccant ETHYLE ACETATE and stir under nitrogen.(9.12g 45.1mmol) and with reaction flask cools off through ice bath to drip DIAD.With reaction solution stirred overnight at room temperature.(18.53ml 226mmol) joins in the reaction mixture and with reaction solution stirred overnight at room temperature with water and dense HCl.Water and DCM are joined in the reaction mixture, stir and isolate water.Merge with organic phase water extracted twice and with water.The water that merges use the DCM washed twice, with the pH of water through adding NaOH be adjusted to～12.Water is used the DCM extracted twice, with the DCM phase water washed twice that merges.Organic phase is evaporated to dry doubling product is passed through purification by flash chromatography.Yield 31.8%. 1H-NMR(400MHz；DMSO)：δ1.42(d，3H)，2.80-3.00(m，2H)，4.27-4.38(m，1H)，7.03(d，1H)，7.84-7.95(m，2H)，8.00(m，1H)。
B) (S)-5-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propyl group) different
Figure BDA0000157427790001671
azoles-3-methane amide
(S)-method that 5-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propyl group) different
Figure BDA0000157427790001672
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (500mg; 1.794mmol) and 5-ethanoyl different
Figure BDA0000157427790001673
(417mg 2.69mmol) prepares as raw material azoles-3-formic acid.Product is passed through purification by flash chromatography twice (positive and anti-phase).Yield 19.6%. 1H-NMR(400MHz；DMSO)：δ1.51(d，3H)，2.57(s，3H)，3.56-3.77(m，2H)，4.65-4.77(m，1H)，7.01(d，1H)，7.56(s，1H)，7.89(dd，1H)，7.91(d，1H)，7.98(s，1H)，9.03(t，1H)。
Embodiment 203
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(5-methyl furan-2-yl) different
Figure BDA0000157427790001674
azoles-3-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(5-methyl furan-2-yl) different
Figure BDA0000157427790001675
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (150mg; 0.575mmol) and 5-(5-methyl-furans-2-yl)-different
Figure BDA0000157427790001676
(111mg 0.575mmol) prepares as raw material azoles-3-formic acid.Product is passed through purification by flash chromatography.Yield 41.5%. 1H-NMR(400MHz；MeOD)：δ1.28(d，3H)，2.38(dd，3H)，4.27-4.45(m，2H)，4.54-4.63(m，1H)，6.23-6.26(m，1H)，6.66(s，1H)，6.77(d，1H)，6.91(td，1H)，7.71(d，1H)，7.75(dd，1H)，7.86(dd，1H)，8.05(dd，1H)。
Embodiment 204
(S)-N-(2-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propyl group)-2-methyl isophthalic acid H-imidazoles-4-methane amide
(S)-method that N-(2-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propyl group)-2-methyl isophthalic acid H-imidazoles-4-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (1.0g; 3.59mmol) and 2-methyl isophthalic acid H-imidazoles-(0.498g 3.95mmol) prepares as raw material 4-formic acid.Product is passed through purification by flash chromatography twice (positive and anti-phase).Yield 8.2%. 1H-NMR(400MHz；DMSO)：δ1.45(d，3H)，2.27(s，3H)，3.50-3.74(m，2H)，4.62-4.77(m，1H)，7.02(d，1H)，7.45(s，1H)，7.88-8.04(m，4H)，12.11(s，1H)。
Embodiment 205
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-pyrazoles-4-yl) thiazole-4-carboxamide
(300mg, 2.359mmol) (433mg 2.60mmol) is dissolved in exsiccant THF under nitrogen with 3-bromo-2-oxo propionic acid with 1H-pyrazoles-4-carbothioic acid carbothiolic acid acid amides.Reaction mixture was heated 3 hours down at 60 ℃.Reaction mixture is cooled to room temperature and is evaporated to dried.(300mg 1.151mmol) joins in the reaction flask and utilizes the method for embodiment 34 (d) to prepare title compound with DCM with (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Product is developed through purification by flash chromatography and with methyl alcohol.Yield 13.7%. 1H-NMR(400MHz；DMSO)：δ1.17(d，3H)，4.31-4.54(m，3H)，6.96(d，1H)，7.84(d，1H)，7.87(d，1H)，7.94(dd，1H)，8.00(bs，1H)，8.06(d，1H)，8.08(d，1H)，8.38(d，1H)，8.40(bs，1H)，13.38(s，1H)。
Embodiment 206
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-pyrazoles-4-yl) thiazole-4-carboxamide
(1.0g, 7.86mmol) (1.44g 8.65mmol) is dissolved in exsiccant THF under nitrogen with 3-bromo-2-oxo propionic acid with 1H-pyrazoles-4-carbothioic acid carbothiolic acid acid amides.Reaction mixture was heated 4.5 hours down at 60 ℃.Reaction mixture is cooled to room temperature and is evaporated to dried.(1.367g 5.24mmol) joins in the reaction flask and utilizes the method for embodiment 34 (d) to prepare title compound with DCM with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile.Product is developed through purification by flash chromatography and with acetonitrile.Yield 37.7%. 1H-NMR(400MHz；DMSO)：δ1.11(d，3H)，4.25-4.48(m，3H)，6.89(d，1H)，7.77(d，1H)，7.80(d，1H)，7.87(dd，1H)，7.93(bs，1H)，7.99(d，1H)，8.01(s，1H)，8.31(d，1H)，8.33(bs，1H)，13.31(bs，1H)。
Embodiment 207
N-((S)-1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
(8.21mg 0.217mmol) joins in the flask under nitrogen atmosphere with Peng Qinghuana.Add exsiccant ethanol and mixture is stirred.(45mg, exsiccant ethanolic soln 0.108mmol) also at room temperature stirred mixture 2.5 hours slowly to add (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide.The pH of reaction mixture is adjusted to through adding 1M HCl～2 and mixture is evaporated to dried.Product is passed through purification by flash chromatography.Yield 57.5%. 1H-NMR(400MHz；DMSO)：δ1.13(d，3H)，1.37(d，3H)，4.22-4-51(m，3H)，4.73-4.85(m，1H)，5.38(d，1H)，6.39(s，1H)，6.99(d，1H)，7.82(d，1H)，7.86(d，1H)，7.97(d，1H)，8.09(d，1H)，13.00(s，1H)
Embodiment 208
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-methoxyl group different
Figure BDA0000157427790001691
azoles-5-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-methoxyl group different
Figure BDA0000157427790001692
azoles-5-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (350mg; 1.342mmol) and the 3-methoxyl group-different
Figure BDA0000157427790001693
(250mg 1.745mmol) prepares as raw material azoles-5-formic acid.Product is passed through purification by flash chromatography.Yield 66.0%. 1H-NMR(400MHz；MeOD)：δ1.28(d，3H)，3.98(s，3H)，4.26-4.42(m，2H)，4.49-4.60(m，1H)，6.50(s，1H)，6.77(d，1H)，7.69(d，1H)，7.77(dd，1H)，7.86(dd，1H)，8.01(dd，1H)。
Embodiment 209
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(hydroxymethyl) different azoles-3-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(hydroxymethyl) different azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.675mmol) and 5-(hydroxymethyl) different (126mg 0.878mmol) prepares as raw material azoles-3-formic acid.Product is developed through purification by flash chromatography twice (positive and anti-phase) and with diethyl ether.Yield 1.9%. 1H-NMR(400MHz；MeOD)：δ1.26(d，3H)，4.28-4-43(m，2H)，4.52-4.63(m，1H)，4.68(d，2H)，6.57(t，1H)，6.77(d，1H)，7.70(d，1H)，7.78(dd，1H)，7.88(dd，1H)，8.07(dd，1H)。
Embodiment 210
(R)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
A) (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile
(R)-method that 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile utilizes embodiment 202 is with 2-chloro-6-fluoro-4-(1H-pyrazole-3-yl) benzonitrile (5.0g; 22.56mmol) and (R)-(7.91g 45.1mmol) prepares as raw material carbamate the tertiary butyl (1-hydroxy propane-2-yl).Product is evaporated to dried.Yield 70.5%. 1H-NMR(400MHz；DMSO)：δ0.96(d，3H)，3.20-3.30(m，1H)，4.00-4.10(m，2H)，7.03(d，1H)，7.85-7.91(m，2H)，7.99(m，1H)。
B) (R)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
(R)-method that N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-methyl isophthalic acid H-imidazoles-4-methane amide utilizes embodiment 34 (d) is with (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (1.0g; 3.59mmol) and 2-methyl isophthalic acid H-imidazoles-(0.50g 3.95mmol) prepares as raw material 4-formic acid.Product is passed through purification by flash chromatography twice (positive and anti-phase).Yield 10.4%. 1H-NMR(400MHz；DMSO)：δ1.07(d，3H)，2.30(s，3H)，4.22-4.50(m，3H)，7.02(d，2H)，7.42(d，1H)，7.86(d，1H)，7.93(dd，1H)，8.00(d，1H)，8.07(d，1H)，12.11(bs，1H)。
Embodiment 211
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methyl isophthalic acid; 3,4-two
Figure BDA0000157427790001711
azoles-2-methane amide
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methyl isophthalic acid; 3; 4-
Figure BDA0000157427790001712
diazole-2-methane amide utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.652mmol) and the 5-methyl isophthalic acid; 3; (100mg 0.782mmol) prepares as raw material diazole-2-formic acid 4-
Figure BDA0000157427790001713
.Product is passed through purification by flash chromatography twice (positive and anti-phase).Yield 3.7%. 1H-NMR(400MHz；MeOD)：δ1.28(d，3H)，2.58(s，3H)，4.30-4.44(m，2H)，4.53-4.64(m，1H)，6.76-6.78(m，1H)，7.71(d，1H)，7.76-7.80(m，1H)，7.86-7.90(m，1H)，8.02-8.04(m，1H)。
Embodiment 212
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-ethoxyethyl group) thiazole-4-carboxamide
A) 2-(1-ethoxyethyl group) thiazole-4-formic acid
(0.277g 4.93mmol) joins in the flask and stirring with ethanol with Pottasium Hydroxide.(0.5g is 3.29mmol) and with the reaction mixture stirred overnight to add 2-bromine propionic acid amide.Mixture is filtered and filtrating is evaporated to dried.With 2,4-two (4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphorus heterocycle butane-2,4-disulphide (Lawensson ' s reagent) (0.665g 1.643mmol) joins in the evaporation residue and with mixture to descend to heat 2 hours at 60 ℃ with THF.Reaction mixture is evaporated to dried.(0.604g 3.62mmol) joins in the evaporation residue and with mixture to descend to heat 3 hours at 60 ℃ with THF with the acid of 3-martonite.Reaction mixture is cooled to room temperature and is evaporated to dried.Product is passed through purification by flash chromatography.Yield 102%. 1H-NMR(400MHz；DMSO)：δ1.16(t，3H)，1.46(d，3H)，3.79-3.86(m，2H)，4.78(q，1H)，8.42(s，1H)。
B) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-ethoxyethyl group) thiazole-4-carboxamide
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-ethoxyethyl group) thiazole-4-carboxamide utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (350mg; 1.342mmo) and 2-(1-ethoxyethyl group) thiazole-(661mg 3.28mmol) prepares as raw material 4-formic acid.Product is passed through purification by flash chromatography (anti-phase).Yield 31.7%. 1H-NMR(400MHz；MeOD)：δ1.19-1.24(m，3H)，1.26(dd，3H)，1.51(t，3H)，3.48-3.58(m，1H)，3.58-3.66(m，1H)，4.33-4.46(m，2H)，4.52-4.62(m，1H)，4.72-4.79(m，1H)，6.77(dd，1H)，7.70-7.72(m，1H)，7.75-7.79(m，1H)，7.85-7.89(m，1H)，8.02(m，1H)，8.08(d，1H)。
Embodiment 213
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(sulfonyloxy methyl amino methyl) different azoles-3-methane amide
A) (S)-5-(amino methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001722
azoles-3-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(sulfonyloxy methyl amino methyl) different
Figure BDA0000157427790001723
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (300mg; 1.151mmol) and 5-{ [(tert-butoxycarbonyl) amino] methyl different
Figure BDA0000157427790001724
(362mg 1.496mmol) prepares as raw material azoles-3-formic acid.With reaction mixture water washed twice, drying also is evaporated to dried.10%HCl/ ethanolic soln (5.2ml) is joined in this evaporation residue and with mixture stirred overnight at room temperature.With reaction mixture evaporation, add DCM and water and with the pH of water through adding 5%NaHCO 3Be adjusted to～7.Isolate organic phase, with water washing and be evaporated to the dried title compound that obtains.Product is passed through purification by flash chromatography.Yield 14.5%. 1H-NMR(400MHz；MeOD)：δ1.26(d，3H)，3.93(d，2H)，4.28-4.43(m，2H)，4.53-4.63(m，1H)，6.55(t，1H)，6.76(d，1H)，7.70(d，1H)，7.78(dd，1H)，7.89(dd，1H)，8.07(dd，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(sulfonyloxy methyl amino methyl) different
Figure BDA0000157427790001731
azoles-3-methane amide
(25mg 0.065mmol) joins in the flask with DCM and stirring under nitrogen with (S)-5-(amino methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001732
azoles-3-methane amide.(9.05 μ l 0.065mmol) and with reaction mixture at room temperature stirred 1 hour to add methylsulfonyl chloride.Add methylsulfonyl chloride (6 μ l) and with reaction mixture stirred overnight at room temperature.Add methylsulfonyl chloride (16 μ l) and reaction mixture was at room temperature stirred 3 days.Reaction mixture is evaporated to dry doubling to be developed product with acetonitrile.Yield 8.3%. 1H-NMR(400MHz；DMSO)：δ1.16(d，3H)，2.94(s，3H)，4.26-4.53(m，5H)，6.64(s，1H)，6.94(d，1H)，7.82(d，1H)，7.86(m，1H)，7.92(dd，1H)，7.98(d，1H)，8.09(d，1H)，8.81(d，1H)
Embodiment 214
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-methyl isophthalic acid H-pyrazoles-5-yl) different
Figure BDA0000157427790001733
azoles-3-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-methyl isophthalic acid H-pyrazoles-5-yl) different
Figure BDA0000157427790001734
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.69mmol) and 5-(1-methyl isophthalic acid H-pyrazoles-5-yl) different (173mg 0.898mmol) prepares as raw material azoles-3-formic acid.Product is passed through to develop and purifying with acetonitrile and methyl alcohol.Yield 28.2%. 1H-NMR(400MHz；DMSO)：δ1.19(d，3H)，4.06(s，3H)，4.35(d，2H)，4.43-4.57(m，1H)，6.91(d，1H)，6.96(d，1H)，7.20(s，1H)，7.59(d，1H)，7.85(d，1H)，7.93(dd，1H)，7.97(d，1H)，8.09(d，1H)，8.94(d，1H)。
Embodiment 215
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxycyclopent base) different
Figure BDA0000157427790001741
azoles-3-methane amide
(S)-method that N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxycyclopent base) different
Figure BDA0000157427790001742
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.69mmol) and 5-(1-hydroxycyclopent base) different
Figure BDA0000157427790001743
(173mg 0.878mmol) prepares as raw material azoles-3-formic acid.Product is passed through purification by flash chromatography twice (positive and anti-phase).Yield 23.2%. 1H-NMR(400MHz；MeOD)：δ1.26(d，3H)，1.75-2.12(m，8H)，4.28-4.44(m，2H)，4.52-4.64(m，1H)，6.51(s，1H)，6.77(d，1H)，7.70(d，1H)，7.77(dd，1H)，7.88(dd，1H)，8.09(dd，1H)。
Embodiment 216
(S)-the 5-tertiary butyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001744
azoles-3-methane amide
(S)-method that the 5-tertiary butyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001745
azoles-3-methane amide utilizes embodiment 34 (d) is with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.69mmol) and the 5-tertiary butyl different
Figure BDA0000157427790001746
(132mg 0.782mmol) prepares as raw material azoles-3-formic acid.Product is passed through purification by flash chromatography (anti-phase).Yield 53.6%. 1H-NMR(400MHz；MeOD)：δ1.26(d，3H)，1.35(s，9H)，4.26-4.45(m，2H)，4.51-4.63(m，1H)，6.34(s，1H)，6.77(d，1H)，7.70(d，1H)，7.77(dd，1H)，7.87(dd，1H)，8.09(dd，1H)。
Embodiment 217
(S)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
A) (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-(trifluoromethyl) benzonitrile
Title compound is from 4-(1H-pyrazoles-5-yl)-2-(trifluoromethyl) benzonitrile (1.4g; 5.90mmol), (R)-tertiary butyl 2-hydroxy propyl carbamate (1.03g; 5.90mmol), triphenylphosphine (2.32g; 8.85mmol) and tert-butyl azodicarboxylate (2.04g 8.85mmol) utilizes the method preparation of embodiment 34 (c).Yield 0.429g. 1H?NMR(400MHz；MeOD)：δ1.52(d，3H)，2.98(dd，1H)，3.12(dd，1H)，4.43(m，1H)，6.87(d，1H)，7.77(d，1H)，7.98(m，1H)，8.21(m，1H)，8.33(m，1H)。
B) (S)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-(trifluoromethyl) benzonitrile (429mg; 1.45mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (225mg; 1.45mmol), HOBt (236mg, 1.75mmol), DIPEA (0.305mL, 1.75mmol) and EDCI (335mg; 1.75mmol) utilize DCM to utilize the method for embodiment 34 (d) to prepare as solvent, obtain the 483mg title compound. 1H?NMR(400MHz；d 6-DMSO)：δ1.50(d，3H)，2.47(s，3H)，3.63(m，2H)，4.69(m，1H)，7.03(d，1H)，7.25(bs，1H)，7.90(d，1H)，8.18(m，2H)，8.27(m，1H)，14.15(bs，1H)。
Embodiment 218
(R)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
A) (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-(trifluoromethyl) benzonitrile
Title compound is from 4-(1H-pyrazoles-5-yl)-2-(trifluoromethyl) benzonitrile (1.32g; 5.55mmol), (S)-tertiary butyl 2-hydroxy propyl carbamate (0.97g; 5.55mmol), triphenylphosphine (2.18g; 8.33mmol), (1.92g 8.33mmol) utilizes the method preparation of embodiment 34 (c) to tert-butyl azodicarboxylate.Yield 0.381g. 1H?NMR(400MHz；MeOD)：δ1.52(d，3H)，2.98(dd，1H)，3.12(dd，1H)，4.43(m，1H)，6.87(d，1H)，7.77(d，1H)，7.98(m，1H)，8.21(m，1H)，8.33(m，1H)。
B) (R)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
Title compound is from (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2-(trifluoromethyl) benzonitrile (381mg; 1.3mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (200mg; 1.3mmol), HOBt (210mg, 1.55mmol), DIPEA (0.271mL, 1.55mmol) and EDCI (298mg; 1.55mmol) utilize DCM to utilize the method for embodiment 34 (d) to prepare as solvent, obtain the 410mg title compound. 1H?NMR(400MHz；d 6-DMSO)：δ1.50(d，3H)，2.47(s，3H)，3.63(m，2H)，4.69(m，1H)，7.03(d，1H)，7.25(bs，1H)，7.90(d，1H)，8.18(m，2H)，8.27(m，1H)，14.15(bs，1H)。
Embodiment 219
(S)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2, and (380mg, 1.45mmol) (229mg 1.48mmol) utilizes the method for embodiment 34 (d) to prepare to 6-difluoro benzonitrile with 3-ethanoyl-1H-pyrazoles-5-formic acid.Yield 249mg. 1H?NMR(400MHz；d 6-DMSO)：δ1.49(d，3H)，2.48(s，3H)，3.62(m，2H)，4.67(m，1H)，6.98(d，1H)，7.25(bs，1H)，7.76(m，2H)，7.89(d，1H)，8.52(bs，1H)，14.18(bs，1H)。
Embodiment 220
N-((R)-2-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propyl group)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
(R)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide (0.1g with embodiment 218; 0.232mmol) (0.018g 0.465mmol) utilizes the method for embodiment 84 to react with Peng Qinghuana.The yield 0.059g of title compound. 1HNMR(400MHz；CDCl 3)：δ1.55(d，3H)，1.61(d，3H)，3.77(m，1H)，3.90(m，1H)，4.64(m，1H)，5.03(q，1H)，6.60(s，1H)，6.65(d，1H)，7.44(bs，1H)，7.51(d，1H)，7.83(d，1H)，8.06(dd，1H)，8.32(s，1H)，10.40(bs，1H)。
Embodiment 221
(R)-2-amino-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group) thiazole-4-carboxamide
Title compound is from (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2; 6-difluoro benzonitrile (380mg; 1.45mmol), thiazolamine-4-formic acid (217mg, 1.5mmol), HOBt (235mg, 1.74mmol), DIPEA (0.303mL; 1.74mmol) and EDCI (333mg 1.74mmol) utilizes DCM to utilize the method preparation of embodiment 34 (d) as solvent.Yield 92mg. 1HNMR(400MHz；CDCl 3)：δ1.60(d，3H)，3.81(m，2H)，4.61(m，1H)，4.91(s，2H)，6.60(d，1H)，7.37(s，1H)，7.50(d，1H)，7.58(m，2H)，7.80(m，1H)。
Embodiment 222
(R)-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-2-(cyano methyl) thiazole-4-carboxamide
A) 2-(cyano methyl) thiazole-4-formic acid
(2g 19.97mmol) stirs under nitrogen in excessive THF (40mL) with (cyanic acid) thioacetamide.Solution is cooled to 0 ℃ also drips the acid of 3-martonite (3.33g, solution 19.97mmol) that is dissolved in 5mL THF.Mixture was refluxed 3 hours.Evaporating solvent and with crude product through purification by flash chromatography (silica gel, eluent: the 0-40%DCM-10%MeOH/DCM mixture) obtain the 1.615g title compound. 1H?NMR(400MHz；CDCl 3)：δ4.20(s，2H)，8.33(s，1H)。
B) (R)-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-2-(cyano methyl) thiazole-4-carboxamide
Title compound is from (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2,6-difluoro benzonitrile (380mg, 1.45mmol) and 2-(cyano methyl) thiazole-4-formic acid (244mg 1.45mmol) utilizes the method preparation of embodiment 34 (d).Yield 70mg. 1H?NMR(400MHz；d 6-DMSO)：δ1.47(d，3H)，3.29(s，2H)，3.67(m，2H)，4.74(m，1H)，6.99(d，1H)，7.77(m，2H)，7.92(d，1H)，8.25(d，1H)，8.44(m，1H)。
Embodiment 223
N-((R)-1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
A) (R)-3-ethanoyl-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2, and (733mg, 2.79mmol) (431mg 2.79mmol) utilizes the method for embodiment 34 (d) to prepare to 6-difluoro benzonitrile with 3-ethanoyl-1H-pyrazoles-5-formic acid.Yield 121mg. 1H?NMR(400MHz；d 6-DMSO)：δ1.49(d，3H)，2.48(s，3H)，3.63(m，2H)，4.67(m，1H)，6.98(d，1H)，7.25(bs，1H)，7.76(m，2H)，7.89(d，1H)，14.16(s，1H)。
B) N-((R)-1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
Title compound is from (R)-3-ethanoyl-N-(1-(3-(4-cyanic acid-3; The 5-difluorophenyl)-and the 1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide (90mg; 0.226mmol) and Sodium Borohydride (17mg 0.452mmol) utilizes the method preparation of embodiment 84.Yield 41mg. 1H?NMR(400MHz；CDCl 3)：δ1.57(d，3H)，1.59(d，3H)，4.26(m，1H)，4.45(m，1H)，4.58(m，1H)，5.06(q，1H)，6.61(m，2H)，7.50(d，1H)，7.58(m，2H)，7.73(bs，1H)，10.44(s，1H)。
Embodiment 224
(S)-3-ethanoyl-N-(1-(4-chloro-3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 2-chloro-4-(4-chloro-1H-pyrazoles-5-yl) benzonitrile hydrochloride
With 2-chloro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile (12.0g, 41.7mmol) be dissolved in acetate (20ml) and add the chlorine bleach liquor (29.0ml, 416mmol).With reaction mixture stirred overnight at room temperature.Add acetate (120ml) and chlorine bleach liquor (14ml) and with mixture stirred overnight at room temperature.Throw out is filtered and water and DCM washing.Throw out is obtained 5.8g 2-chloro-4-(4-chloro-1H-pyrazoles-5-yl) benzonitrile 40 ℃ of following drying under vacuum overnight.(5.8g, 24.36mmol) (167ml, mixture 365mmol) at room temperature stirred 2 hours, and throw out is filtered and use water washing with the 10%HCl/ ethanolic soln with 2-chloro-4-(4-chloro-1H-pyrazoles-5-yl) benzonitrile.Throw out is obtained the 4.0g crude product with the ethanol pulp.Product is obtained totally 18% title compound with purification by flash chromatography. 1H?NMR(400MHz；d 6-DMSO)：δ8.05(m，2H)，8.16(m，2H)。
B) (S)-4-(1-(2-aminopropyl)-4-chloro-1H-pyrazole-3-yl)-2-benzyl chloride nitrile
Title compound is from 2-chloro-4-(4-chloro-1H-pyrazoles-5-yl) benzonitrile (0.690g; 2.9mmol), (S)-tertiary butyl 1-hydroxy propane-2-aminocarbamic acid ester (0.508g; 2.9), triphenylphosphine (1.14g; 4.35mmol) and tert-butyl azodicarboxylate (1g 4.35mmol) utilizes the method preparation of embodiment 34 (c).Yield 0.518g. 1H?NMR(400MHz；CDCl 3)：δ1.16(d，3H)，1.32(bs，2H)，3.47(m，1H)，3.88(dd，1H)，4.09(dd，1H)，7.56(s，1H)，7.69(d，1H)，7.99(dd，1H)，8.13(d，1H)。
C) (S)-3-ethanoyl-N-(1-(4-chloro-3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-4-chloro-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (518mg; 1.75mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (270mg; 1.75mmol), HOBt (285mg, 2.1mmol), DIPEA (0.367mL, 2.1mmol) and EDCI (404mg; 2.1mmol) utilize DCM to utilize the method for embodiment 34 (d) to prepare as solvent, obtain the 382mg title compound. 1H?NMR(400MHz；d 6-DMSO)：δ1.15(d，3H)，2.42(s，3H)，4.30(m，2H)，4.44(m，1H)，6.86(s，1H)，8.01(m，3H)，8.12(s，1H)。
Embodiment 225
(S)-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
A) 3-(pyridin-3-yl)-1H-pyrazoles-5-ethyl formate
(0.2g 13.69mmol) is dissolved in 12ml ethanol fully under nitrogen with sodium.In this solution, add the 3-acetylpyridine (1.499ml, 13.69mmol), under constant agitation, at room temperature add then oxalic acid diethyl ester (1.859ml, 13.69mmol).Then mixture was heated 3 hours down at 75 ℃.Then mixture is cooled to room temperature and adds hydrazonium salt hydrochlorate (0.938g, water 13.69mmol) (2ml) solution.Once more solution was heated 3 hours down at 75 ℃.After LC-MS confirmation reaction completion, neutralize with the reaction mixture cooling and through 2M NaOH solution.Then crude product is used ethyl acetate extraction, water and brine wash.Pass through CombiFlash purifying (eluent: DCM:10%MeOH/DCM) with organic solvent evaporation and with resistates.Yield 1.577g. 1H?NMR(400MHz；MeOD)：δ1.40(t，3H)，4.39(q，2H)，7.29(s，1H)，7.51(m，1H)，8.24(m，1H)，8.51(dd，1H)，8.99(d，1H)。
B) 3-(pyridin-3-yl)-1H-pyrazoles-5-formic acid
With 3-(pyridin-3-yl)-1H-pyrazoles-5-ethyl formate (1.577g, ethanol 7.26mmol) (60ml) and THF (60ml) solution and 1M NaOH solution (40ml, 7.26mmol) reaction and 60 ℃ of down heating 2 hours.Solvent evaporated under reduced pressure and with residue diluted with water.Solution is passed through to add the acidifying of 2N HCl solution.The mixture that forms was stirred in ice bath 4 hours and solid sediment is filtered, and drying is also weighed.Yield 378mg. 1H?NMR(400MHz；d 6-DMSO)：δ7.39(m，2H)，8.21(d，1H)，8.53(bs，1H)，9.06(bs，1H)。
C) (S)-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2; 6-difluoro benzonitrile (0.277g; 1.06mmol), 3-(pyridin-3-yl)-1H-pyrazoles-5-formic acid (0.2g, 1.06mmol), HOBt (0.17g, 1.27mmol), DIPEA (0.22mL; 1.27mmol) and EDCI (0.243g 1.27mmol) utilizes DCM to utilize the method preparation of embodiment 34 (d) as solvent.Yield 0.13g. 1H?NMR(400MHz；d 6-DMSO)：δ1.50(d，3H)，3.66(m，2H)，4.72(m，1H)，7.00(d，1H)，7.20(s，1H)，7.48(m，1H)，7.78(m，2H)，7.93(d，1H)，8.13(m，1H)，8.55(dd，1H)，8.97(s，1H)。
Embodiment 226
(R)-5-ethanoyl-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group) different
Figure BDA0000157427790001811
azoles-3-methane amide
A) (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2,6-difluoro benzonitrile
Title compound is from 2; 6-two fluoro-4-(1H-pyrazoles-5-yl) benzonitrile (3.88g; 18.9mmol), (S)-tertiary butyl 2-hydroxy propyl carbamate (3.31g; 18.9mmol), triphenylphosphine (7.44g, 28.4mmol), (6.53g 28.4mmol) utilizes the method for embodiment 34 (c) to obtain to tert-butyl azodicarboxylate.Yield 2.29g. 1H?NMR(400MHz；MeOD)：δ1.51(d，3H)，2.98(dd，1H)，3.12(m，1H)，4.42(m，1H)，6.84(d，1H)，7.67(m，2H)，7.76(d，1H)。
B) (R)-5-ethanoyl-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group) different azoles-3-methane amide
Title compound is from (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2; 6-difluoro benzonitrile (0.955g; 3.64mmol), 5-ethanoyl different
Figure BDA0000157427790001813
azoles-3-formic acid (0.565g; 3.64mmol), HOBt (0.738g; 5.46mmol), DIPEA (1.9mL, 10.92mmol) and EDCI (1.05g 5.46mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent.Product is obtained the 60mg pure products with the CombiFlash purifying. 1H?NMR(400MHz；CDCl 3)：δ1.63(d，3H)，2.64(s，3H)，3.82(m，1H)，3.95(m，1H)，4.64(m，1H)，6.61(d，1H)，7.29(s，1H)，7.52(m，3H)，7.62(m，1H)。
Embodiment 227
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 2-chloro-3-fluoro-4-(1H-pyrazoles-5-yl) benzonitrile
Title compound from 2-chloro-3-fluoro-4-iodine benzonitrile (0.242g, 0.86mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-boric acid pinacol ester (0.239g, 0.86mmol) utilize embodiment 34 (a) and method (b) preparation.Yield 0.075g. 1H?NMR(400MHz；MeOD)：δ6.84(dd，1H)，7.59(m，2H)，7.79(s，1H)，8.08(bs，1H)。
B) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile
Title compound is from 2-chloro-3-fluoro-4-(1H-pyrazoles-5-yl) benzonitrile (0.075g; 0.34mmol) and (S)-tertiary butyl (1-hydroxy propane-2-yl) carbamate (0.059g; 0.34mmol) utilize the method for embodiment 34 (c) to prepare, obtain the 0.051g title product. 1H?NMR(400MHz；CDCl 3)：δ1.15(d，3H)，1.34(bs，2H)，3.49(m，1H)，3.95(dd，1H)，4.16(dd，1H)，6.79(dd，1H)，7.48(m，1H)，7.52(d，1H)，8.07(m，1H)。
C) (S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.05g; 0.18mmol) and 3-ethanoyl-1H-pyrazoles-5-formic acid (0.028g 0.18mmol) utilizes DMF (3mL) to utilize the method preparation of embodiment 34 (d) as solvent.Yield 0.056g. 1H?NMR(400MHz；CDCl 3)：δ1.16(d，3H)，2.46(s，3H)，4.29(m，2H)，4.49(m，1H)，6.70(dd，1H)，7.17(bs，1H)，7.50(m，2H)，8.06(m，1H)。
Embodiment 228
(S)-3-ethanoyl-N-(1-(3-(3,5-two chloro-4-cyano-phenyls)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) the 4-bromo-3, the 5-dichlorphenamide bulk powder
With 3, (10g, acetonitrile 61.7mmol) (100mL) solution join and are equipped with TM, condensing surface and contain N-bromo-succinimide that (10.99g is in the 3-neck flask of the tap funnel of acetonitrile 61.7mmol) (30mL) solution the 5-dichlorphenamide bulk powder.Below 5 ℃ N-bromo-succinimide solution is slowly being joined 3 in the flask through keeping internal temperature under 0 ℃, in the 5-dichlorphenamide bulk powder solution.After adding NBS reaction mixture is warming up to room temperature and continues stirring 3 hours.After LC-MS confirmation reaction completion, mixture is used 10%NaHSO 3The aqueous solution (150mL) dilution.With solution stirring 15 minutes and be evaporated to 1/3 of solvent TV.Then with the mixture dilute with water that forms and use ethyl acetate extraction.Organic solvent is dry, and evaporation also obtains pure 4-bromo-3,5-dichlorphenamide bulk powder through the CombiFlash purifying.Yield 13.6g. 1H?NMR(400MHz；d 6-DMSO)：δ5.82(bs，2H)，6.75(s，2H)。
B) 4-amino-2, the 6-DCB
Title compound is through with 4-bromo-3, and (6.88g, 28.6mmol) (2.56g, DMF 28.6mmol) (48mL) solution react down at 190 ℃ under microwave irradiation and obtained in 1 hour the 5-dichlorphenamide bulk powder with cuprous cyanide (I).After reaction is accomplished mixture is cooled to room temperature also with 200ml12% ammonia solution termination reaction.The mixture that forms was at room temperature stirred 30 minutes and throw out is filtered, with water washing and vacuum-drying.Yield 3.725g. 1H?NMR(400MHz；d 6-DMSO)：δ6.70(s，1H)，6.79(s，1H)。
C) 2,6-two chloro-4-iodine benzonitriles
With 4-amino-2, (1.65g 8.82mmol) stirs in 7.5ml 12M HCl solution the 6-DCB.Reaction mixture is cooled off with ice bath.(0.6g 8.82mmol) is added drop-wise in the flask under cooling conditions, drips cold potassiumiodide (5.86g, water 35.3mmol) (12mL) solution then will to be dissolved in the Sodium Nitrite of 6ml water.Mixture was at room temperature stirred 1 day.Reaction is used ethyl acetate extraction with mixture after accomplishing, and uses 10%Na 2SO 3Solution and brine wash.Organic layer is used anhydrous Na 2SO 4Dry also evaporation.The solid that obtains is washed and vacuum-drying with heptane-ethyl acetate mixture (5: 1).Yield 1.09g. 1H?NMR(400MHz；d 6-DMSO)：δ6.71(s，1H)，6.81(s，1H)。
D) 2,6-two chloro-4-(1H-pyrazoles-5-yl) benzonitrile hydrochloride
Title compound is from 2,6-two chloro-4-iodine benzonitriles (1.09g, 3.66mmol) and 1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-boric acid pinacol ester (1.32g 4.76mmol) according to embodiment 34 (a) and (b) described method preparation, isolates hydrochloride.Yield 0.824g. 1H?NMR(400MHz；d 6-DMSO)：δ7.07(d，1H)，7.88(d，1H)，8.14(s，2H)。
E) (S)-and 4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2, the 6-DCB
Title compound is from 2,6-two chloro-4-(1H-pyrazoles-5-yl) benzonitrile (0.75g, 3.15mmol) with (S)-(-)-(0.552g 3.15mmol) utilizes the method preparation of embodiment 34 (c) to 2-(tert-butoxycarbonyl is amino)-1-propyl alcohol.Yield 0.121g. 1H?NMR(400MHz；CDCl 3)：δ1.15(d，3H)，1.54(bs，2H)，3.49(m，1H)，3.93(dd，1H)，4.14(dd，1H)，6.60(d，1H)，7.50(d，1H)，7.84(s，2H)。
F) (S)-3-ethanoyl-N-(1-(3-(3,5-two chloro-4-cyano-phenyls)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2; 6-DCB (0.121g; 0.41mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (0.063g, 0.41mmol), HOBt (0.083g, 0.615mmol), DIPEA (0.214mL; 1.23mmol) and EDCI (0.118g 0.615mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent.Yield 6.3mg. 1H?NMR(400MHz；CDCl 3)：δ1.29(d，3H)，2.55(s，3H)，4.36(m，2H)，4.57(m，1H)，6.64(d，1H)，7.40(s，1H)，7.58(d，1H)，7.83(s，2H)。
Embodiment 229
N-((S)-1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
(S)-3-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide (0.05g with embodiment 227; 0.122mmol) (0.009g 0.244mmol) utilizes the method for embodiment 84 to react with Peng Qinghuana.The yield of title compound is 0.015g. 1HNMR(400MHz；MeOD)：δ1.23(d，3H)，1.49(d，3H)，4.39(m，2H)，4.55(m，1H)，6.56(s，1H)，6.77(dd，1H)，7.67(d，1H)，7.75(d，1H)，8.17(m，1H)。
Embodiment 230
(S)-N-(1-(3-(4-cyanic acid-3; The 5-difluorophenyl)-and the 1H-pyrazol-1-yl) propane-2-yl)-3-sec.-propyl-1; 2,4-
Figure BDA0000157427790001841
diazole-5-methane amide
A) 3-sec.-propyl-1; 2,4-
Figure BDA0000157427790001842
diazole-5-formic acid
Title compound is from 3-sec.-propyl-1; 2; 4-
Figure BDA0000157427790001851
diazole-5-ethyl formate (0.4g, 2.17mmol) and sodium hydroxide solution (6mL) utilize the method preparation of embodiment 225 (b).Yield 0.25g. 1H?NMR(400MHz；D 2O)：δ1.33(d，6H)，3.17(m，1H)。
B) (S)-N-(1-(3-(4-cyanic acid-3; The 5-difluorophenyl)-and the 1H-pyrazol-1-yl) propane-2-yl)-3-sec.-propyl-1; 2,4- diazole-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2; 6-difluoro benzonitrile (0.168g; 0.64mmol), 3-sec.-propyl-1,2,4-
Figure BDA0000157427790001853
diazole-5-formic acid (0.1g; 0.64mmol), HOBt (0.13g; 0.96mmol), DIPEA (0.335mL, 1.92mmol) and EDCI (0.184g 0.96mmol) utilizes DMF to utilize the method preparation of embodiment 34 (d) as solvent.The yield of title compound is 5mg. 1H?NMR(400MHz；MeOD)：δ1.27(d，3H)，1.36(d，6H)，3.16(m，1H)，4.39(m，2H)，4.58(m，1H)，6.80(d，1H)，7.62(m，2H)，7.72(d，1H)。
Embodiment 231
N-((R)-2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-5-(1-hydroxyethyl) different
Figure BDA0000157427790001854
azoles-3-methane amide
(R)-5-ethanoyl-N-(2-(3-(4-cyanic acid-3 with embodiment 226; The 5-difluorophenyl)-and the 1H-pyrazol-1-yl) propyl group) different
Figure BDA0000157427790001855
azoles-3-methane amide (0.047g; 0.136mmol) (0.010g 0.272mmol) utilizes embodiment 84 described method reactions with Peng Qinghuana.The yield of title compound is 0.045g. 1H?NMR(400MHz；MeOD)：δ1.50(dd，3H)，1.59(d，3H)，3.75(m，2H)，4.93(m，1H)，6.53(m，1H)，6.79(d，1H)，7.67(m，2H)，7.73(d，1H)。
Embodiment 232
N-((R)-1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different azoles-3-methane amide
A) (R)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001857
azoles-3-methane amide
Title compound is from (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2; 6-difluoro benzonitrile (0.214g; 0.81mmol) and 5-ethanoyl different
Figure BDA0000157427790001861
azoles-3-formic acid (0.127g 0.81mmol) utilizes the method preparation of embodiment 34 (d).Yield 0.166g. 1H?NMR(400MHz；MeOD)：δ1.28(d，3H)，2.59(s，3H)，4.37(m，2H)，4.60(m，1H)，6.80(d，1H)，7.27(s，1H)，7.64(m，2H)，7.72(d，1H)。
B) N-((R)-1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different azoles-3-methane amide
According to embodiment 84 described methods with raw material (R)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3; The 5-difluorophenyl)-and the 1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001863
azoles-3-methane amide (0.147g; 0.4mmol) and Peng Qinghuana (0.03g, 0.8mmol) reaction obtains the 0.135g title product. 1H?NMR(400MHz；MeOD)：δ1.26(d，3H)，1.51(dd，3H)，4.36(m，2H)，4.57(m，1H)，4.94(m，1H)，6.52(m，1H)，6.79(d，1H)，7.65(m，2H)，7.71(d，1H)。
Embodiment 233
(S)-5-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) different azoles-3-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.4g; 1.43mmol), 5-ethanoyl different
Figure BDA0000157427790001865
azoles-3-formic acid (0.223g; 1.43mmol), HOBt (0.291g; 2.15mmol), DIPEA (0.75mL; 4.31mmol) and EDCI (0.413g 2.15mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent.Yield 47mg.LC-MS:m/z [M+H +] C 19H 15ClFN 5O 3 +Calculated value: 415.8; Measured value: 415.9.
Embodiment 234
N-((S)-1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl) different
Figure BDA0000157427790001866
azoles-3-methane amide
(S)-5-ethanoyl-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790001867
azoles-3-methane amide (0.04g with embodiment 233; 0.096mmol) (0.007g 0.192mmol) utilizes the method for embodiment 84 to react with Peng Qinghuana.The yield of title compound is 0.023g. 1HNMR(400MHz；MeOD)：δ1.26(d，3H)，1.51(dd，3H)，4.38(m，2H)，4.59(m，1H)，4.94(m，1H)，6.52(m，1H)，6.77(dd，1H)，7.63(m，1H)，7.74(m，1H)，8.12(m，1H)。
Embodiment 235
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(morpholino methyl)-1H-pyrazoles-5-methane amide
A) 3-(morpholino methyl)-1H-pyrazoles-5-ethyl formate
Title compound from 1-morpholino propane-2-ketone (4.192g, 29.3mmol), sodium (0.43g, 29.3mmol), (4.28g, 29.3mmol) (2g 29.3mmol) utilizes the method preparation of embodiment 225 (a) to oxalic acid diethyl ester with the hydrazonium salt hydrochlorate.Yield 18%. 1H?NMR(400MHz；CDCl 3)：δ1.39(t，3H)，2.48(m，4H)，3.60(d，2H)，3.71(m，4H)，4.38(q，2H)，6.74(s，1H)。
B) 3-(morpholino methyl)-1H-pyrazoles-5-formic acid
Title compound from 3-(morpholino methyl)-1H-pyrazoles-5-ethyl formate (0.138g, 0.57mmol) and sodium hydroxide solution (2mL) utilize the method preparation of embodiment 225 (b).Yield 0.119g. 1HNMR(400MHz；MeOD)：δ3.22(m，2H)，3.46(m，2H)，3.78(m，2H)，4.05(m，2H)，4.43(s，2H)，7.05(s，1H)。
C) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(morpholino methyl)-1H-pyrazoles-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.147g; 0.56mmol), 3-(morpholino methyl)-1H-pyrazoles-5-formic acid (0.119g; 0.56mmol), HOBt (0.114; 0.84mmol), DIPEA (0.29mL, 1.69mmol) and EDCI (0.162g 0.84mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent.Yield 0.256g. 1H?NMR(400MHz；MeOD)：δ1.24(d，3H)，2.44(m，4H)，3.59(s，2H)，3.67(m，4H)，4.35(m，2H)，4.55(m，1H)，6.62(bs，1H)，6.74(d，1H)，7.69(d，1H)，7.76(d，1H)，7.88(m，1H)，8.00(m，1H)。
Embodiment 236
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(morpholino methyl) different azoles-3-methane amide
A) 5-(morpholino methyl) different azoles-3-ethyl formate
To chloro glyoxylic acid oxime ethyl ester (0.588g, 3.88mmol) and 4-(Propargyl) morpholine (0.971g drips triethylamine (0.54mL, toluene 3.88mmol) (5mL) solution in toluene 7.76mmol) (5mL) solution.The mixture that forms was at room temperature stirred 5 hours.After confirming that through LC-MS reaction is accomplished, with the reaction mixture dilute with water and use ethyl acetate extraction.Then organic solvent is also evaporated with anhydrous sodium sulfate drying.Crude product is passed through CombiFlash purifying (heptane: the EtOAc eluent).Yield 0.2g. 1H?NMR(400MHz；MeOD)：δ1.38(t，3H)，2.53(m，4H)，3.69(m，4H)，3.78(d，2H)，4.41(q，2H)，6.73(m，1H)。
B) 5-(morpholino methyl) different
Figure BDA0000157427790001883
azoles-3-formic acid
Title compound from 5-(morpholino methyl) different
Figure BDA0000157427790001884
azoles-3-ethyl formate (0.2g, 0.85mmol) and sodium hydroxide solution (2mL) utilize the method preparation of embodiment 225 (b).Yield 0.25g. 1H?NMR(400MHz；D 2O)：δ3.46(m，4H)，3.99(m，4H)，4.72(s，2H)，7.10(m，1H)。
C) (S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(morpholino methyl) different
Figure BDA0000157427790001885
azoles-3-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.2g; 0.72mmol), 5-(morpholino methyl) different
Figure BDA0000157427790001886
azoles-3-formic acid (0.15g; 0.72mmol), HOBt (0.145g; 1.07mmol), DIPEA (0.37mL; 2.15mmol) and EDCI (0.2g 1.07mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent.Yield 72mg. 1H?NMR(400MHz；d 6-DMSO)：δ1.17(d，3H)，2.39(m，4H)，3.56(m，4H)，3.71(s，2H)，4.34(m，2H)，4.46(m，1H)，6.62(s，1H)，6.76(m，1H)，7.83(m，1H)，7.88(d，1H)，8.03(m，1H)。
Embodiment 237
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-3-yl)-1; 2,4-
Figure BDA0000157427790001891
diazole-5-methane amide
A) 3-(pyridin-3-yl)-1; 2,4-
Figure BDA0000157427790001892
diazole-5-formic acid
According to US 5578550 about preparation 3-sec.-propyl-1; 2; 4-
Figure BDA0000157427790001893
diazole-described method of 5-ethyl formate is from (E)-N '-pyridone-3-carbonamidine (2.727g; 19.88mmol) and ethyl oxalyl chloride (2.89mL; 25.9mmol) preparation, use sodium hydroxide solution to carry out the ester hydrolysis subsequently according to the method for embodiment 225 (b).Yield 1.32g. 1H?NMR(400MHz；d 6-DMSO)：δ7.63(m，1H)，8.32(m，1H)，8.86(dd，1H)，9.03(dd，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-3-yl)-1; 2,4-
Figure BDA0000157427790001894
diazole-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.2g; 0.72mmol), 3-(pyridin-3-yl)-1; 2; 4-
Figure BDA0000157427790001895
diazole-5-formic acid (0.137g, 0.72mmol), HOBt (0.145g, 1.07mmol), DIPEA (0.375mL; 2.15mmol) and EDCI (0.2g 1.07mmol) utilizes DMF to utilize the method preparation of embodiment 34 (d) as solvent.Yield 33.4mg. 1H?NMR(400MHz；d 6-DMSO)：δ1.23(d，3H)，4.41(m，2H)，4.52(m，1H)，6.79(m，1H)，7.65(m，1H)，7.78(m，1H)，7.95(d，1H)，8.03(m，1H)，8.38(m，1H)，8.83(dd，1H)，9.19(dd，1H)，9.51(m，1H)。
Embodiment 238
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(pyridin-3-yl)-1; 2,4- diazole-5-methane amide
Title compound according to the method for embodiment 34 (d) from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.27g; 1.05mmol), 3-(pyridin-3-yl)-1; 2, and 4-
Figure BDA0000157427790001897
diazole-5-formic acid (0.2g, 1.05mmol), HOBt (0.21g; 1.57mmol), DIPEA (0.55mL; 3.14mmol) and EDCI (0.3g 1.57mmol) utilizes DMF to prepare as solvent, obtains the 54mg title product. 1H?NMR(400MHz；d 6-DMSO)：δ1.23(d，3H)，4.37(m，2H)，4.50(m，1H)，6.96(d，1H)，7.65(m，1H)，7.88(d，1H)，7.92(m，2H)，8.04(m，1H)，8.38(m，1H)，8.83(dd，1H)，9.19(dd，1H)，9.50(m，1H)。
Embodiment 239
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-imidazo [2,1-b] thiazole-6-methane amide
A) imidazo [2,1-b] thiazole-6-ethyl formate
To ice-cold thiazolamine (0.5g, add in 10ml DME solution 4.99mmol) ethyl bromide acetone (0.783mL, 6.24mmol).The mixture that forms was at room temperature stirred 30 minutes.The yellow mercury oxide that obtains is filtered.Solid residue is dissolved in 20ml ethanol and refluxed 8 hours.Confirm that through LC-MS reaction completion final vacuum is except that desolvating.Resistates joined among the DCM and with sodium hydrogen carbonate solution wash.Pass through the Combiflash purifying with organic solvent evaporation and with crude product.Yield 0.285g. 1H?NMR(400MHz；CDCl 3)：δ1.42(t，3H)，4.41(q，2H)，6.98(d，1H)，7.47(d，1H)，8.09(s，1H)。
B) imidazo [2,1-b] thiazole-6-formic acid
Title compound prepares from 0.285g imidazo [2,1-b] thiazole-6-ethyl formate and 2ml sodium hydroxide solution according to the method for embodiment 225 (b).Yield 0.379g. 1H?NMR(400MHz；D 2O)：δ7.53(d，1H)，7.98(d，1H)，8.31(s，1H)。
C) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [2,1-b] thiazole-6-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.31g; 1.19mmol), imidazo [2,1-b] thiazole-6-formic acid (0.2g, 1.19mmol), HOBt (0.24g; 1.78mmol), DIPEA (0.62mL; 3.57mmol) and EDCI (0.34g 1.78mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent, obtains the 232mg product. 1H?NMR(400MHz；MeOD)：δ1.24(d，3H)，4.38(m，2H)，4.55(m，1H)，6.76(d，1H)，7.21(d，1H)，7.75(m，3H)，7.90(dd，1H)，8.06(m，1H)，8.09(s，1H)。
Embodiment 240
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyrimidine-2-methane amide
Title compound utilizes the method for embodiment 34 (d) from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.3g; 1.07mmol), imidazo [1; 2-a] pyrimidine-2-formic acid (0.17g, 1.07mmol), HOBt (0.22g, 1.61mmol), DIPEA (0.56mL; 3.23mmol) and EDCI (0.31g 1.61mmol) utilizes DMF (10mL) to prepare as solvent.Yield 0.29g. 1H?NMR(400MHz；CDCl 3)：δ1.25(d，3H)，4.30(dd，1H)，4.49(dd，1H)，4.65(m，1H)，6.81(dd，1H)，6.98(dd，1H)，7.53(d，1H)，7.73(dd，1H)，8.08(s，1H)，8.48(dd，1H)，8.67(m，3H)。
Embodiment 241
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyrazine-2-methane amide
Title compound according to the described method of embodiment 34 (d) from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.34g; 1.22mmol), imidazo [1; 2-a] pyrazine-2-formic acid (0.2g, 1.22mmol), HOBt (0.25g, 1.84mmol), DIPEA (0.64mL; 3.68mmol) and EDCI (0.35g 1.84mmol) utilizes 10ml DMF to prepare as solvent.Yield 0.26g. 1H?NMR(400MHz；MeOD)：δ1.30(d，3H)，4.44(m，2H)，4.58(m，1H)，6.77(dd，1H)，7.59(dd，1H)，7.78(d，1H)，7.90(d，1H)，8.14(dd，1H)，8.36(d，1H)，8.49(dd，1H)，9.06(bs，1H)。
Embodiment 242
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-sec.-propyl-1; 2,4- diazole-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.36g; 1.28mmol), 3-sec.-propyl-1; 2, and 4-
Figure BDA0000157427790001922
diazole-5-formic acid (0.2g, 1.28mmol), HOBt (0.26g; 1.92mmol); DIPEA (0.67mL, 3.84mmol) and EDCI (0.37g 1.92mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent.Yield 0.144g. 1H?NMR(400MHz；MeOD)：δ1.29(d，3H)，1.34(d，6H)，3.15(m，1H)，4.41(m，2H)，4.58(m，1H)，6.79(dd，1H)，7.62(dd，1H)，7.76(d，1H)，8.08(dd，1H)。
Embodiment 243
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1H-imidazol-4 yl) thiazole-4-carboxamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.3g; 1.07mmol), 2-(1H-imidazol-4 yl) thiazole-4-formic acid (0.25g; 1.29mmol), HOBt (0.22g; 1.61mmol), DIPEA (0.56mL, 3.23mmol) and EDCI (0.31g 1.61mmol) utilizes the preparation of the described method of embodiment 34 (d) with 10mL DMF as solvent.Yield 65mg. 1H?NMR(400MHz；CDCl 3)：δ1.27(d，3H)，4.40(m，2H)，4.60(m，1H)，6.80(dd，1H)，7.24(d，1H)，7.30(m，1H)，7.56(m，2H)，7.70(d，1H)，8.02(s，1H)，8.08(m，1H)。
Embodiment 244
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(morpholino methyl) thiazole-4-carboxamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.3g; 1.07mmol), 2-(morpholino methyl) thiazole-4-formic acid (0.29g; 1.29mmol), HOBt (0.22g; 1.61mmol), DIPEA (0.56mL, 3.23mmol) and EDCI (0.31g 1.61mmol) utilizes the method preparation of embodiment 34 (d) as solvent with 10mL DMF.Yield 0.27g. 1HNMR(400MHz；d 6-DMSO)：δ1.13(d，3H)，3.61(m，4H)，3.84(d，2H)，4.39(m，3H)，6.78(dd，1H)，7.84(dd，1H)，7.90(d，1H)，8.06(dd，1H)，8.15(s，1H)，8.45(d，1H)。
Embodiment 245
N-((S)-1-(3-(3,5-two chloro-4-cyano-phenyls)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
Title compound from (S)-3-ethanoyl-N-(1-(3-(3,5-two chloro-4-cyano-phenyls)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide (63mg, 0.15mmol) and Peng Qinghuana (11mg 0.29mmol) utilizes the method preparation of embodiment 84.Yield 15mg. 1H?NMR(400MHz；CDCl 3)：δ1.23(d，3H)，1.54(d，3H)，4.34(m，2H)，4.54(m，1H)，4.96(q，1H)，6.61(m，2H)，7.52(d，1H)，7.90(m，2H)。
Embodiment 246
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790001931
azoles-3-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-3-fluorine benzonitrile (0.3g; 1.07mmol), 5-(2-hydroxy propane-2-yl) different azoles-3-formic acid (0.22g; 1.29mmol), HOBt (0.22g; 1.61mmol), DIPEA (0.56mL; 3.23mmol) and EDCI (0.31g 1.61mmol) utilizes DMF (10mL) to utilize the method preparation of embodiment 34 (d) as solvent.Yield 40mg. 1H?NMR(400MHz；CDCl 3)：δ1.23(d，3H)，1.62(s，6H)，4.36(m，2H)，4.59(m，1H)，6.57(m，1H)，6.82(dd，1H)，7.54(m，2H)，8.00(m，1H)，8.20(m，1H)。
Embodiment 247
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1H-imidazoles-4-methane amide
(1.00g 8.9mmol) is dissolved in exsiccant DMF (35ml) with the 4-imidazole formic acid.At room temperature add exsiccant 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 2.31g, 12.0mmol), HOBt (1.84g, 12.0mmol) and DIPEA (4.7ml, 3.46g, 26.8mmol).(2.44g, dry DMF (15ml) solution 9.4mmol) at room temperature joins in the solution to stir after 15 minutes (S)-4-[1-(2-aminopropyl)-1H-pyrazole-3-yl]-2-benzyl chloride nitrile with embodiment 34 (c).Then with solution stirring 45 hours.Add entry and product is used ethyl acetate extraction.With salt solution and water washing, drying is also evaporated with organic phase.Crude product is passed through the purifying with hot DCM development.Product is filtered and uses heptane wash. 1H NMR (400MHz, DMSO-d 6): 1.08 (3H, d), 4.30 (1H, distored dd), 4.41 (2H, m), 6.95 (1H, d), 7.57 (1H, s), 7.75 (1H, d), 7.85 (1H, d), 8.01 (2H, m), 8.21 (1H, s), 8.30 (1H, d), 12.47 (1H, wide s).
Embodiment 248
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid H-imidazoles-4-methane amide
(1.364g 10.82mmol) is suspended in N, in the dinethylformamide (25ml) with 2-methyl isophthalic acid H-imidazoles-4-formic acid.With O-(benzotriazole-1-yl)-N; N, N ', N '-tetramethyl-urea hexafluorophosphate (0.342g; 0.901mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.073g; 10.82mmol), DIPEA (3.14ml, 18.03mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(2.5g 9.01mmol) joins in the mixture respectively 2-benzyl chloride nitrile 4-fast.With reaction mixture stirred overnight at room temperature.Slowly added entry in second day and mixture is used the DCM extracted twice.Evaporate with the organic phase water extraction three times that merges and with the DCM layer.Product is used the acetonitrile/water mixture crystallization, at last 40 ℃ of following vacuum-dryings.Yield 71.6%. 1H-NMR(400MHz；d6-DMSO)：δ1.08(d，3H)，2.31(s，3H)，4.27(dd，1H)，4.32-4.48(m，2H)，6.95(d，1H)，7.41(s，1H)，7.82(d，1H)，7.95-8.02(m，2H)，8.04(d，1H)，8.10(m，1H)，12.10(bs，1H)。
Embodiment 249
(S)-N-{1-[3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid H-imidazoles-4-methane amide
Title compound according to the method for embodiment 247 with 2-methyl isophthalic acid H-imidazoles-4-formic acid with (S)-4-[1-(2-aminopropyl)-1H-pyrazole-3-yl]-2-chloro-6-fluorine benzonitrile (its can according to the method preparation of embodiment 34 (c)) prepares as raw material.Crude product through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-98: 2) obtain product, it is at room temperature developed with diethyl ether obtain title compound. 1H NMR (400MHz, DMSO-d 6): 1.06 (3H, d), 2.31 (3H, s), 4.28 (1H, distored dd), 4.35-4.45 (2H, m), 7.02 (1H, d), 7.42 (1H, s), 7.86 (1H, d), 7.93 (1H, dd), 8.00 (1H, d), 8.07 (1H, d), 12.11 (1H, s).
Embodiment 250
(S)-N-{2-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propyl group }-2-methyl isophthalic acid H-imidazoles-4-methane amide
The method that title compound utilizes embodiment 247 with 2-methyl isophthalic acid H-imidazoles-4-formic acid with (S)-4-[1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl]-2-benzyl chloride nitrile prepares as raw material.With crude product through at room temperature developing and purifying with DCM. 1H NMR (400MHz, DMSO-d 6): 1.44 (3H, d), 2.27 (3H, s), 3.57 (1H, m), 3.67 (1H, m), 4.68 (1H, m), 6.96 (1H, d), 7.44 (1H, s), 7.89 (1H, d), 7.95-7.99 (3H, m), 8.12 (1H, s), 12.1 (1H, wide s).
Embodiment 251
(R)-N-{2-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propyl group }-2-methyl isophthalic acid H-imidazoles-4-methane amide
A) (R)-tertiary butyl 2-hydroxy propyl carbamate
(10.17g, DCM solution (30ml) 46.6mmol) slowly join (R)-(-)-1-amino-2-propyl alcohol, and (3.67ml is in DCM 46.6mmol) (60ml) solution with tert-Butyl dicarbonate.At room temperature continue after the stirred overnight reaction mixture to be diluted (200ml) also with water washing (2x100ml) with DCM.Organic layer is dry, and filtration and evaporation obtain title compound. 1H NMR (400MHz, CDCl 3): 1.18 (3H, d), 1.45 (9H, s), 2.47 (1H, wide s), 3.00 (1H, m), 3.26 (1H, m), 3.90 (1H, m), 4.96 (1H, wide s)
B) (R)-4-[1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl]-2-benzyl chloride nitrile
(R)-method that 4-[1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl]-2-benzyl chloride nitrile utilizes embodiment 34 (c) with 2-chloro-4-(1H-pyrazole-3-yl) benzonitrile with (R)-tertiary butyl 2-hydroxy propyl carbamate prepares as raw material. 1H NMR (400MHz, CDCl 3): 1.24 (2H, wide s), 1.54 (3H, d), 3.05 (1H, distored dd), 3.17 (1H, distored dd), 4.34 (1H, m), 6.61 (1H, d), 7.52 (1H, d), 7.66 (1H, d), 7.78 (1H, dd), 7.98 (1H, d).
C) (R)-N-{2-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propyl group }-2-methyl isophthalic acid H-imidazoles-4-methane amide
(R)-N-{2-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propyl group-method that 2-methyl isophthalic acid H-imidazoles-4-methane amide utilizes embodiment 247 with 2-methyl isophthalic acid H-imidazoles-4-formic acid with (R)-4-[1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl]-2-benzyl chloride nitrile prepares as raw material.Crude product through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2-MeOH (98: 2) is as eluent.The product that forms at room temperature developed with DCM carry out purifying and obtain title compound. 1H NMR (400MHz, CDCl 3): 1.61 (3H, d), 2.39 (3H, s), 3.74-3.81 (1H, m), 3.85-3.91 (1H, m), 4.63 (1H; M), 6.59 (1H, d), 7.45 (1H, d), 7.49 (1H, d), 7.62 (1H, t); 7.66 (1H, d), 7.84 (1H, dd), 8.00 (1H, d), 10.04 (1H, wide s).
Embodiment 252
(S)-N-{1-[3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-methyl isophthalic acid H-imidazoles-4-methane amide
The method that title compound utilizes embodiment 247 with 1-methyl isophthalic acid H-imidazoles-4-formic acid with (S)-4-[1-(2-aminopropyl)-1H-pyrazole-3-yl]-2-chloro-6-fluorine benzonitrile (it is according to method preparation of embodiment 34 (c)) prepares as raw material.Crude product through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-99: 1).The product that forms at room temperature developed with diethyl ether obtain title product. 1H NMR (400MHz, DMSO-d 6): 1.21 (3H, d), 3.74 (3H, s), 4.26 (1H, distored dd), 4.42 (1H, distored dd), 4.56 (1H, m), 6.60 (1H, d), 7.43 (1H, d), 7.49 (1H, d), 7.50 (1H, d), 7.75 (1H, dd), 7.87 (1H, m), 7.97 (1H, d).
Embodiment 253
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-ethyl-1H-imidazoles-4-methane amide
With (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1H-imidazoles-4-methane amide (250mg; 0.705mmol) dry DMF (3ml) solution under nitrogen, slowly join dry DMF (1ml) and 55%NaH at 0 ℃ (61.4mg be in mixture 1.41mmol).Then reaction mixture was at room temperature stirred 30 minutes.Reaction mixture is cooled to 0 ℃ again.0 ℃ add down slowly iodoethane (0.057ml, 0.712mmol), then with reaction mixture stirred overnight at room temperature.With reaction mixture with salt solution (20ml) termination reaction, with pH be adjusted to more than 9 with NaOH and with product with ethyl acetate extraction (3x 30ml).The organic layer that merges is used water washing, dry and concentrated.Carry out flash chromatography on silica gel, use CH 2Cl 2-MeOH is as gradient elution agent (100: 0-99: 1) obtain title product. 1H NMR (400MHz, DMSO-d 6): 1.07 (3H, d), 1.34 (3H, t), 4.02 (2H, q), 4.20 (1H, distored dd), 4.34 (2H, m), 6.95 (1H, d), 7.67 (1H, d), 7.76 (1H, d), 7.84 (1H, d), 8.00 (2H, m), 8.20 (1H, d), 8.27 (1H, d).
Embodiment 254
(S)-and N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1,2-dimethyl--1H-imidazoles-4-methane amide
With (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid H-imidazoles-4-methane amide (700mg; 1.90mmol), EtOH (22ml), KOH (151mg; 2.70mmol) and methyl iodide (0.26ml; 593mg 4.18mmol) joins in the microwave oven reaction flask.Reaction mixture was at room temperature stirred 74 hours.Add entry and solution evaporation is extremely dried then.Add entry once more, throw out is filtered and water and heptane wash.Carry out flash chromatography on silica gel, utilize CH 2Cl 2-MeOH is as gradient elution agent (100: 0-99: 1) obtain product, it with ETHYLE ACETATE crystallization again, is at room temperature filtered and obtain title compound with heptane wash. 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 2.39 (3H, s), 3.60 (3H, s), 4.29 (1H, distored dd), 4.38 (1H; Distored dd), 4.55 (1H, m), 6.60 (1H, d), 7.41 (1H, s), 7.48 (1H, d); 7.54 (1H, d), 7.66 (1H, d), 7.85 (1H, dd), 7.99 (1H, d).
Embodiment 255
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-4-methane amide
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-method that 1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-4-methane amide utilizes embodiment 253 is with (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid H-imidazoles-4-methane amide and 2-iodopropane prepare as raw material. 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 1.43 (6H, d), 2.42 (3H, s), 4.29 (2H, m), 4.39 (1H, distored dd), 4.57 (1H, m), 6.61 (1H, d), 7.49 (1H, d), 7.56 (1H, s), 7.59 (1H, d), 7.66 (1H, d), 7.86 (1H, dd), 8.00 (1H, d).
Embodiment 256
(S)-N-{2-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propyl group }-1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-4-methane amide
Title compound utilizes the method for embodiment 253 with (S)-N-{2-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propyl group }-2-methyl isophthalic acid H-imidazoles-4-methane amide and 2-iodopropane prepare as raw material. 1H?NMR(400MHz，CDCl 3)：1.42(3H，d)，1.43(3H，d)，1.60(3H，d)，2.37(3H，s)，3.77(1H，m)，3.88(1H，m)，4.28(1H，m)，4.63(1H，m)，6.58(1H，d)，7.50(1H，d)，7.51(1H，t)，7.59(1H，s)，7.66(1H，d)，7.84(1H，dd)，8.00(1H，d)。
Embodiment 257
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-(3-oxo butyl)-1H-imidazoles-4-methane amide
With (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1H-imidazoles-4-methane amide (600mg; 1.69mmol) and methyl vinyl ketone (0.42ml; 5.18mmol) (7 μ l are in DMSO 0.085mmol) (6ml) solution to join the 1-Methylimidazole.Reaction mixture was stirred 11 hours down at 70 ℃.Add entry then and product is used ethyl acetate extraction.The organic layer that merges is used water washing, dry and concentrated.Crude product through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-98: 2) obtain title compound. 1H NMR (400MHz, CDCl 3): 1.21 (3H, d), 2.16 (3H, s), 2.92 (2H, t), 4.26 (2H, t); (4.28 1H, distored dd), 4.39 (1H, distored dd), 4.56 (1H, m), 6.60 (1H, d); 7.48 (1H, d), 7.50 (1H, d), 7.52 (1H, d), 7.66 (1H; Distored d), 7.79 (1H, distored dd), 7.86 (1H, d), 8.17 (1H, d).
Embodiment 258
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid-(3-oxo butyl)-1H-imidazoles-4-methane amide
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-method that 2-methyl isophthalic acid-(3-oxo butyl)-1H-imidazoles-4-methane amide utilizes previous embodiment is with (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid H-imidazoles-4-methane amide and methyl vinyl ketone prepare as raw material. 1H NMR (400MHz, CDCl 3): 1.21 (3H, d), 2.17 (3H, s), 2.44 (3H, s), 2.89 (2H, t); 4.13 (2H, t), 4.29 (1H, distored dd), 4.38 (1H, distored dd), 4.55 (1H, m); 6.60 (1H, d), 7.44 (1H, s), 7.48 (1H, d), 7.58 (1H; D), 7.66 (1H, distored d), 7.85 (1H, distored dd), 8.00 (1H, d).
Embodiment 259
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-(3-hydroxy-3-methyl butyl)-1H-imidazoles-4-methane amide
With (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-(100mg, exsiccant THF (3ml) solution 1.18mmol) joins under 30-40 ℃ in the diethyl ether solution (0.39ml) of 3.0M methyl-magnesium-bromide 1-(3-oxo butyl)-1H-imidazoles-4-methane amide.Then reaction mixture was stirred 3 hours down at 45 ℃.The refrigerative reaction mixture is poured in the saturated NH4Cl solution.Evaporating solvent is also used ethyl acetate extraction with product.The organic layer that merges is used water washing, dry and concentrated.Through the flash chromatography on silica gel purifying, utilize EtOAc-MeOH (9: 1) crude product as eluent.Carry out last purifying through preparation HPLC and obtain title compound. 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 1.30 (6H, s), 1.97 (2H, m), 4.14 (2H; M), 4.28 (1H, distored dd), 4.41 (1H, distored dd), 4.56 (1H, m); 6.60 (1H, d), 7.48 (2H, m), 7.56 (1H, d), 7.61 (1H; Distored d), 7.79 (1H, distored dd), 7.86 (1H, d), 8.17 (1H, d).
Embodiment 260
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-(3-hydroxy-3-methyl butyl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
Title compound utilizes the method for previous embodiment with (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid-(3-oxo butyl)-1H-imidazoles-4-methane amide and methyl-magnesium-bromide prepare as raw material.Crude product through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 1-98: 2).Carry out last purifying through preparation HPLC and obtain title compound. 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 1.30 (6H, s), 1.65 (1H, wide s), 1.88 (2H, m); 2.42 (3H, s), 4.02 (2H, m), 4.30 (1H, distored dd), 4.38 (1H, distored dd); 4.55 (1H, m), 6.60 (1H, d), 7.47 (1H, s), 7.50 (1H, d); 7.62 (1H, d), 7.65 (1H, d), 7.84 (1H, dd), 7.99 (1H, d).
Embodiment 261
N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-(3-hydroxybutyl)-1H-imidazoles-4-methane amide
With Peng Qinghuana (9.8mg; 0.26mmol) at room temperature join (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl-(100mg is in ethanol 0.24mmol) (3ml) solution for 1-(3-oxo butyl)-1H-imidazoles-4-methane amide.Then reaction mixture was at room temperature stirred 3 hours.Add entry then and product is used ethyl acetate extraction.The organic layer that merges is also dry with water washing.Evaporating solvent obtains title compound. 1H NMR (400MHz, CDCl 3): 1.21 (3H, d), 1.22 (3H, d), 1.89 (2H, m), 2.31 (1H, wide s); 3.73 (1H, m), 4.15 (2H, m), 4.28 (1H, distored dd), 4.40 (1H, distored dd); 4.56 (1H, m), 6.61 (1H, d), 7.51 (2H, m), 7.60 (1H, d); (7.66 1H, distored d), 7.79 (1H, m), 7.95 (1H, d), 8.18 (1H, d).
Embodiment 262
N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-(3-hydroxybutyl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
Title compound utilizes the method for previous embodiment with (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid-(3-oxo butyl)-1H-imidazoles-4-methane amide prepares as raw material. 1H NMR (400MHz, CDCl 3): 1.22 (6H, d), 1.81 (2H, m), 2.41 (1H, m), 2.45 (1H, wide s); 3.74 (1H, m), 4.03 (2H, m), 4.30 (1H, distored dd), 4.38 (1H, distored dd); 4.55 (1H, m), 6.60 (1H, d), 7.51 (1H, d), 7.53 (1H, s); 7.65 (1H, d), 7.66 (1H, d), 7.85 (1H, dd), 7.99 (1H, d).
Embodiment 263
N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-[(2-methyl oxirane-2-yl) methyl]-1H-imidazoles-4-methane amide and 1-(3-chloro-2-hydroxy-2-methyl propyl group)-N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1H-imidazoles-4-methane amide
With (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1H-imidazoles-4-methane amide (120mg, 0.338mmol), 2-(chloromethyl)-2-methyl oxirane (2.88g, 27.1mmol and Y (NO 3) 3X 6H 2(3.6mg, mixture 0.0093mmol) stirred 30 minutes down in 120 ℃ under MW O.Behind the evaporation oxyethane resistates is passed through the flash chromatography on silica gel purifying, utilize CH 2Cl 2-MeOH as the gradient elution agent (100: 0-99: 1) obtain primary product N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-[(2-methyl oxirane-2-yl) methyl]-1H-imidazoles-4-methane amide and secondary product 1-(3-chloro-2-hydroxy-2-methyl propyl group)-N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl-1H-imidazoles-4-methane amide.
N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-[(2-methyl oxirane-2-yl) methyl]-1H-imidazoles-4-methane amide: 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 1.31 (3H, s), 2.58 and 2.77 (2 diastereomers, 1H, d), 4.08 and 4.35 (2 diastereomers; 1H, distored dd), 4.57 (1H, m), (1H, distored dd), 6.62 (1H, d); 7.50 (1H, d), 7.51 (1H, s), 7.59 (1H, d), 7.66 (1H; Distored d), 7.79 (1H, distored dd), 7.97 (1H, d), 8.20 (1H, d).
1-(3-chloro-2-hydroxy-2-methyl propyl group)-N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1H-imidazoles-4-methane amide: 1H NMR (400MHz, CDCl 3): 1.20 (2 diastereomers, 3H, m), 1.34 and 1.35 (2 diastereomers, 3H, s), 3.31-3.42 (2 diastereomers, 2H, m); 3.99-4.18 (2 diastereomers, 2H, m), 4.21-4.43 (2 diastereomers, 3H, m), 4.54 (1H, m); 6.61 (1H, d), 7.49 (1H, d), 7.57 (1H, s), 7.66 (1H, distored d); 7.76 (1H, s), 7.78 (1H, m), 8.15 (1H, d), 8.20 (1H, d).
Embodiment 264
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-(pyridine-2-yl)-1H-imidazoles-4-methane amide
In the microwave oven reaction tube, add CuI (5.5mg; 0.028mmol), 1H-benzotriazole (6.7mg; 0.056mmol), DMSO (1ml), 2-bromopyridine (0.054ml, 89mg, 0.566mmol), (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl-1H-imidazoles-4-methane amide (200mg; 0.564mmol) and KOt-Bu (89mg, 0.789mmol).Reaction mixture was stirred 30 minutes in microwave oven under 150 ℃.Then mixture is cooled to room temperature, adds entry and product is used ethyl acetate extraction.The organic layer that merges is also dry with water washing.Behind the evaporating solvent resistates is passed through the flash chromatography on silica gel purifying, utilize CH 2Cl 2-MeOH is as gradient elution agent (100: 0-99: 1).Obtain required product with the diethyl ether development. 1H NMR (400MHz, CDCl 3): 1.26 (3H, d), 4.29 (1H, distored dd), 4.45 (1H, distored dd), 4.61 (1H, m); 6.62 (1H, d), 7.32 (1H, dd), 7.38 (1H, d), 7.50 (1H, d); 7.66 (1H, d), 7.81 (1H, dd), 7.88 (1H, td), 8.00 (1H; M), 8.18 (2H, m), 8.42 (1H, s), 8.53 (1H, d).
Embodiment 265
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-1-(pyridin-3-yl)-1H-imidazoles-4-methane amide
Under nitrogen, in reaction flask, add K 2CO 3(78mg, 0.564mmol), CuI (10.7mg, 0.056mmol), 1; 3-two (2-pyridyl)-1; 3-propane diketone (12.8mg, 0.056mmol), (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl-1H-imidazoles-4-methane amide (200mg, 0.564mmol), exsiccant DMF (4ml) and 3-bromopyridine (0.054ml; 89mg, 0.564mmol).Reaction mixture was stirred 4 hours down at 130 ℃.(0.025ml, 41mg 0.260mmol), continue heating 2 hours down at 130 ℃ then to add the 3-bromopyridine.Then reaction mixture is cooled to room temperature and passes through short siliceous earth column.After rinsed, the filtrating that merges is washed with saturated brine, dry and concentrated.Resistates through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2-MeOH (98: 2) is as eluent.Use CH 2Cl 2-Et 2The O recrystallization obtains required product. 1H NMR (400MHz, CDCl 3): 1.25 (3H, d), 4.29 (1H, distored dd), 4.46 (1H, distored dd), 4.62 (1H, m); 6.64 (1H, d), 7.50 (1H, m), 7.51 (1H, d), 7.68 (1H, distored d); 7.74 (1H, m), 7.80 (1H, distored dd), 7.87 (1H, d), 7.91 (1H, d); 8.11 (1H, d), 8.24 (1H, d), 8.71 (1H, dd), 8-78 (1H, d).
Embodiment 266
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-2-methyl isophthalic acid-(pyridin-3-yl)-1H-imidazoles-4-methane amide
In nitrogen downhill reaction flask, add K 2CO 3(94mg, 0.678mmol), CuI (12.9mg, 0.068mmol), 1; 3-two (2-pyridyl)-1; 3-propane diketone (15.3mg, 0.068mmol), (S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl-2-methyl isophthalic acid H-imidazoles-4-methane amide (250mg, 0.678mmol), exsiccant DMF (5ml) and 3-bromopyridine (0.065ml; 107mg, 0.678mmol).Reaction mixture was stirred 2 hours down at 130 ℃.(0.070ml, 115mg 0.727mmol), continue heating 4 hours down at 140 ℃ then to add the 3-bromopyridine.Add once more the 3-bromopyridine (0.070ml, 115mg, 0.727mmol) and under microwave, continuing heating 1 hour under 170 ℃.Then reaction mixture is cooled to room temperature and passes through short siliceous earth column.After rinsed, the filtrating that merges is washed with saturated brine, dry and concentrated.Resistates through the flash chromatography on silica gel purifying, is utilized CH 2Cl 2-MeOH is as gradient elution agent (99.5: 0.5-98: 2). 1H NMR (400MHz, CDCl 3): 1.25 (3H, d), 2.40 (3H, s), 4.32 (1H, distored dd), 4.43 (1H, distored dd); 4.61 (1H, m), 6.63 (1H, d), 7.50 (1H, m), 7.52 (1H, d); 7.64 (1H, s), 7.66 (1H, m), 7.67 (1H, d), 7.78 (1H, d); 7.87 (1H, dd), 8.03 (1H, d), 8.64 (1H, d), 8.74 (1H, dd).
Embodiment 267
(S)-and N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl } imidazo [1,2-a] pyridine-2-carboxamide
According to the method for embodiment 247 but replace the 4-imidazole formic acid to obtain title compound with imidazo [1,2-a] pyridine-2-formic acid () of WO2005/030704.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-99: 1), at room temperature develop with diethyl ether then. 1H NMR (400MHz, CDCl 3): 1.28 (3H, d), 4.33 (1H, distored dd), 4.45 (1H, distored dd), 4.64 (1H, m); 6.61 (1H, d), 6.87 (1H, td), 7.28 (1H, td), 7.51 (1H, d); 7.60 (1H, dd), 7.64 (1H, d), 7.84 (1H, dd), 8.02 (1H; S), 8.04 (1H, d), 8.12 (1H, d), 8.15 (1H, dt).
Embodiment 268
(S)-and N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-5,6,7, the 8-imidazolidine is [1,2-a] pyridine-2-carboxamide also
According to the method for embodiment 247 but with 5,6,7,8-imidazolidine also [1,2-a] pyridine-2-formic acid (according to WO 2007/108750 from imidazo [1,2-a] pyridine-2-formic acid preparation) replaces the 4-imidazole formic acid to obtain title compound.Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH (98: 2) is as eluent. 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 1.94-2.04 (4H, m), 2.87 (2H, m), 3.99 (2H, t), 4.30 (1H, distored dd); (4.38 1H, distored dd), 4.55 (1H, m), 6.60 (1H, d), 7.40 (1H, s), 7.48 (1H; D), 7.55 (1H, d), 7.66 (1H, d), 7.86 (1H, dd), 7.99 (1H, d).
Embodiment 269
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-3-sec.-propyl-1H-pyrazoles-5-methane amide
According to the method for embodiment 247 but replace the 4-imidazole formic acid to obtain title compound with 5-sec.-propyl-1H-pyrazoles-3-formic acid (according to the WO03/037432A1 preparation).Crude product through purification by flash chromatography, is utilized CH 2Cl 2-MeOH is as gradient elution agent (100: 0-98: 2). 1H NMR (400MHz, CDCl 3): 1.22 (3H, d), 1.30 (6H, d), 3.03 (1H, m), 4.27 (1H; Distored dd), 4.43 (1H, distored dd), 4.58 (1H, m), 6.59 (1H, s); 6.61 (1H, d), 7.50 (1H, d), 7.67 (1H, distored d), 7.76 (1H; Distored dd), 7.85 (1H, d), 8.19 (1H, d), 10.21 (1H, wide s).
Embodiment 270
(S)-N-{1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl }-3-vinyl-1H-pyrazoles-5-methane amide
With triethylamine (3.0ml; 21.8mmol) under 0 ℃, join N-{ (S)-1-[3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl] propane-2-yl of embodiment 56-(1.74g is in DCM 4.36mmol) (40ml) solution for 3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide.Then 0 ℃ add down slowly methylsulfonyl chloride (0.675ml, 8.73mmol).After at room temperature continuing stirred overnight, reaction mixture is washed with the DCM dilution and with 1M HCl.With the dry (Na of organic layer 2SO 4), filter and concentrate.Obtain title compound with the DCM crystallization. 1H NMR (400MHz, CDCl 3+ 1 MeOH-d 4): 1.25 (3H, d), 4.31 (1H, distored dd), 4.39 (1H, distored dd), 4.55 (1H; M), 5.38 (1H, d), 5.76 (1H, d), 6.60 (1H, dd); 6.63 (1H, d), 6.79 (1H, s), 7.55 (1H, d), 7.70 (1H; Distored d), 7.73 (1H, d), 7.82 (1H, distored dd), 7.96 (1H, d).
Embodiment 271
3-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) different
Figure BDA0000157427790002061
azoles-5-yl) ethyl)-1H-pyrazoles-5-methane amide
A) 2-chloro-4-formyl radical-3-methyl benzonitrile
With 2-chloro-4-iodo-3-methyl benzonitrile (150g, 0.54mol) and the mixture of THF (1200ml) be cooled to-32 ℃.(541ml 1.08mol) and with mixture stirred 2 hours down at-32 ℃ in 1 hour, slowly to add 2M i-PrMgCl-THF solution.(83ml 1.08mol) and with reaction mixture is warming up to room temperature to add DMF down at-32 ℃.Add 10%HCl solution (1000ml) down at 0 ℃ after the stirred overnight.Layering and with water layer with diethyl ether extraction (2x 900ml).The organic layer that merges is used saturated NaHCO 3Solution (900ml) and salt solution (750ml) washing.Organic layer is used Na 2CO 4Drying is filtered and evaporation.With exsiccant crude product (95g) with hot normal heptane and activated carbon treatment.Obtain yellow solid shape title compound, it can use without being further purified. 1H-NMR(400MHz；CDCl 3)：δ2.78(s，3H)，7.71(d，1H)，7.84(d，1H)，10.36(s，1H)。
B) (E)-2-chloro-4-((oxyimino) methyl)-3-methyl benzonitrile
(5.0g 27.8mmol) is dissolved in exsiccant THF (60ml) with 2-chloro-4-formyl radical-3-methyl benzonitrile.With pyridine (6.7ml, 84.0mmol) and hydroxy amine hydrochloric acid salt (3.87g 55.7mmol) joins in the solution.With mixture heating up to 70 ℃ and stirred 4 hours.With THF evaporation and adding frozen water (50ml).Mixture was stirred 1 hour and throw out is leached, with twice of cold water washing.Obtain title compound (5.3g) after the drying. 1H-NMR(400MHz；d6-DMSO)：δ2.48(s，3H)，7.79(m，2H)，8.45(s，1H)，11.93(s，1H)。
C) (Z)-3-chloro-4-cyanic acid-N-hydroxy-2-methyl benzimidoyl chlorine
(0.64g 3.27mmol) is dissolved in DMF (20ml) and be cooled to 0 ℃ with (E)-2-chloro-4-((oxyimino) methyl)-3-methyl benzonitrile.(0.48g 3.60mmol) and with mixture is warming up to room temperature to add N-neoprene imide.With mixture stirred overnight and pouring in the frozen water (100ml) at room temperature, use the EtOAc extracted twice, with organic phase water and brine wash, use anhydrous Na 2SO 4Drying is filtered and evaporation.Crude product (0.69g) is not purified can be used. 1H-NMR(400MHz；d6-DMSO)：δ2.42(s，3H)，7.64(d，1H)，7.92(d，1H)，12.77(s，1H)。
D) (2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) different
Figure BDA0000157427790002071
azoles-5-yl) ethyl) t-butyl carbamate
(1.0g 4.37mmol) is dissolved in exsiccant DCM (10ml) and also at room temperature adds triethylamine (0.91ml) with fourth-3-alkynes-1-aminocarbamic acid tert-butyl ester.(1g, DCM 4.37mmol) (5ml) solution joins in the reaction mixture with (2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) different
Figure BDA0000157427790002072
azoles-5-yl) ethyl) t-butyl carbamate.After at room temperature 1 hour, with reaction mixture reflux 6 hours.Add entry (30ml) and water is used dichloromethane extraction, with the organic phase water and the brine wash that merge and use anhydrous Na 2SO 4Drying is filtered and evaporation.Crude product is passed through purification by flash chromatography (toluene-EtOAc3/1), divide merging and evaporation to obtain title compound (0.71g) the product level. 1H-NMR(400MHz；d6-DMSO)：δ1.36(s，9H)，2.48(s，3H)，2.95(t，2H)，3.32(m，2H，)，6.71(s，1H)，7.05(bs，1H)，7.63(d，1H)，7.95(d，1H)。
E) 4-(5-(2-amino-ethyl) different
Figure BDA0000157427790002073
azoles-3-yl)-2-chloro-3-methyl benzonitrile
(0.56g 1.55mmol) is dissolved in DCM (20ml) with (2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) different
Figure BDA0000157427790002074
azoles-5-yl) ethyl) t-butyl carbamate.In this mixture, add TFA (1.15ml) and stirred overnight at room temperature.Reaction mixture is evaporated to dry doubling is dissolved in diethyl ether.Add the diethyl ether solution of 1M HCl and mixture was at room temperature stirred 2 hours.The title compound (0.20g) of HCl salt form is filtered and drying. 1H-NMR(400MHz；d6-DMSO)：δ2.50(s，3H)，2.92(m，2H)，3.22(m，2H)，6.88(s，1H)，7.65(d，1H)，7.98(d，1H)，8.23(bs，3H)。
F) 3-ethanoyl-N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) different
Figure BDA0000157427790002081
azoles-5-yl) ethyl)-1H-pyrazoles-5-methane amide
With 3-ethanoyl-1H-pyrazoles-5-formic acid (31mg; 0.203mmol) and DIPEA (0.106ml) be dissolved in 5ml exsiccant DCM.At room temperature add HOBt hydrate (47mg; 0.304mmol) and EDCI (58mg; 0.304mmol).Add 4-(5-(2-amino-ethyl) different
Figure BDA0000157427790002082
azoles-3-yl)-2-chloro-3-methyl benzonitrile (53mg; 0.203mmol) and reaction solution at room temperature stirred 4 hours.Add 10mlDCM and with organic layer with 1M HCl, saturated NaHCO 3And brine wash.Organic phase is used Na 2SO 4Drying filters and is evaporated to dried.Crude product is obtained the 32mg title product with the normal heptane development. 1H-NMR(400MHz；d6-DMSO)：δ2.44(s，3H)，2.51(s，3H)，3.12(t，2H)，3.63(m，2H)，6.75(s，1H)，7.30(bs，1H)，7.62(d，1H)，7.94(d，1H)，8.73(bs，1H)，14.20(s，1H)。
Embodiment 272
N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) different
Figure BDA0000157427790002083
azoles-5-yl) ethyl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide
N-(2-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl) different
Figure BDA0000157427790002084
azoles-5-yl) ethyl)-3-(pyridin-3-yl)-1H-pyrazoles-5-methane amide is from 4-(5-(2-amino-ethyl) different
Figure BDA0000157427790002085
azoles-3-yl)-2-chloro-3-methyl benzonitrile hydrochloride (54.8g; 0.184mmol), 3-(pyridin-3-yl)-1H-pyrazoles-5-formic acid (34.8mg; 0.184mmol), HOBt hydrate (42.2mg; 0.276mmol), DIPEA (0.096ml; 0.551mmol) and EDCI (53mg, 0.276mmol) utilize DCM as solvent according to the preparation of the described method of previous embodiment.Crude product is obtained title compound 13mg through the preparation HPLC purifying. 1H-NMR(400MHz；CDCl 3)：δ2.47(s，3H)，3.23(t，2H)，3.89(m，2H)，6.30(s，1H)，7.09(bs，1H)，7.22(bs，1H)，7.40(m，2H)，7.57(d，1H)，7.98(d，1H)，8.62(bs，1H)，8.95(bs，1H)。
Embodiment 273
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide
To 1H-pyrazoles-3-formic acid (89mg, at room temperature add in DCM 0.767mmol) (5ml) mixture DIPEA (0.40ml, 2.30mmol), O-(benzotriazole-1-yl)-N; N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU; 291.0mg, 0.767mmol).With mixture stirred 15 minutes and add solid (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg, 0.767mmol).With reaction solution stirred overnight at room temperature.Evaporating solvent also adds entry.The pH regulator of water is extracted with DCM to 9-10 and with product.With organic layer water and brine wash, use Na 2SO 4Dry also evaporation.Crude product is obtained title compound 100mg with purification by flash chromatography (DCM/EtOAc gradient). 1H-NMR(400MHz；d6-DMSO)：δ1.11(d，3H)，4.36(m，3H)，6.58(t，1H)，6.93(d，1H)，7.79(m，1H)，7.82(d，1H)，7.98(d，2H)，8.08(bs，1H)，8.25(d，1H)，13.20(s，1H)。
Embodiment 274
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-4-methyl-2-(pyridin-3-yl)-1H-imidazoles-5-methane amide
With 4-methyl-2-(pyridin-3-yl)-1H-imidazoles-5-formic acid (78mg; 0.384mmol) and DIPEA (0.20ml 1.151mmol) is dissolved in 5ml exsiccant DMF.At room temperature add HOBt hydrate (88mg; 0.575mmol) and EDCI (110mg; 0.575mmol).Disposable adding solid (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (100mg; 0.384mmol), reaction solution was stirred 2 hours down and stirred overnight at room temperature at 60 ℃.Add entry (40ml) and mixture was at room temperature stirred 1 hour.The product that deposition is separated out filters, and obtains title compound 136mg in 12 hours 40 ℃ of following vacuum-dryings. 1H-NMR(400MHz；d6-DMSO)：δ1.12(d，3H)，2.49(s，3H)，4.40(m，3H)，6.97(d，1H)，7.48(m，1H)，7.88(m，2H)，8.02(m，2H)，8.07(d，1H)，8.21(m，1H)，8.58(m，1H)，9.13(d，1H)，12.85(s，1H)。
Embodiment 275
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(4-picoline-3-yl) thiophene-2-carboxamide derivatives
A) 5-(4-picoline-3-yl) thiophene-2-carboxylic acid
(0.200g 0.809mmol) is dissolved in ethanol (5ml) with 5-(4-picoline-3-yl) thiophene-2-carboxylic acid ethyl ester.(0.809ml is 1.617mmol) and with mixture stirred overnight at room temperature to add the 2M sodium hydroxide solution.With ethanol evaporation and add entry (5ml).The product deposition is separated out in the process that adds 2M HCl.Filtering product also, drying obtains the 98mg product. 1H-NMR(400MHz；d6-DMSO)：δ2.43(s，3H)，7.38(d，1H)，7.39(d，1H)，7.77(d，1H)，8.46(d，1H)，8.59(s，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(4-picoline-3-yl) thiophene-2-carboxamide derivatives
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.116g; 0.446mmol), 5-(4-picoline-3-yl) thiophene-2-carboxylic acid (0.098g; 0.446mmol), DIPEA (0.233ml, 1.337mmol), the HOBt hydrate (0.102g, 0.668mmol) and EDCI (0.128g; 0.668mmol) according to the described method preparation of previous embodiment, obtain the 0.115g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.19(d，3H)，2.41(s，3H)，4.32(m，2H)，4.43(m，1H)，6.95(d，1H)，7.33(d，1H)7.37(d，1H)，7.79(d，1H)，7.85(d，1H)，7.94(m，2H)，8.07(d，1H)，8.45(m，2H)，8.55(s，1H)。
Embodiment 276
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(pyridin-3-yl)-1H-pyrazole-3-formamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.058g; 0.307mmol), 1-(pyridin-3-yl)-1H-pyrazoles-3-formic acid (0.080g; 0.307mmol), DIPEA (0.160ml, 0.921mmol), the HOBt hydrate (0.071g, 0.460mmol) and EDCI (0.088g; 0.460mmol) utilize the method for embodiment 274 to prepare, obtain the 0.120g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.18(d，3H)，4.38(m，2H)，4.50(m，1H)，6.89(d，1H)，6.95(d，1H)，7.59(m，1H)，7.90(m，3H)，8.04(d，1H)，8.30(m，1H)，8.38(d，1H)，8.60(d，1H)，8.65(d，1H)，9.19(d，1H)。
Embodiment 277
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3H-imidazo [4,5-b] pyridine-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.063g; 0.384mmol), 3H-imidazo [4,5-b] pyridine-5-formic acid (0.100g, 0.384mmol), DIPEA (0.200ml; 1.151mmol), HOBt hydrate (0.088g; 0.575mmol) and EDCI (0.110g 0.575mmol) utilizes the method preparation of embodiment 274, obtains the 0.130g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.17(d，3H)，4.45(m，3H)，6.93(d，1H)，7.99(m，6H)，8.64(s，1H)，8.99(d，1H)。
Embodiment 278
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(pyridin-4-yl)-1H-pyrazole-3-formamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.058g; 0.307mmol), 1-(pyridin-4-yl)-1H-pyrazoles-3-formic acid (0.080g; 0.307mmol), DIPEA (0.160ml, 0.921mmol), the HOBt hydrate (0.071g, 0.460mmol) and EDCI (0.088g; 0.460mmol) utilize the method for embodiment 274 to prepare, obtain the 0.110g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.19(d，3H)，4.36(m，2H)，4.49(m，1H)，6.90(d，1H)，6.94(d，1H)，7.85(d，1H)，7.90(m，2H)，7.94(m，2H)，8.02(s，1H)，8.38(d，1H)，8.69(m，2H)，8.75(d，1H)。
Embodiment 279
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3H-imidazo [4,5-b] pyridine-5-methane amide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (0.060g; 0.215mmol), 3H-imidazo [4,5b] pyridine-5-formic acid (0.035g, 0.215mmol), DIPEA (0.112ml; 0.646mmol), HOBt hydrate (0.050g; 0.323mmol) and EDCI (0.062g 0.323mmol) utilizes the method preparation of embodiment 274, obtains the 0.050g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.22(d，3H)，4.46(m，3H)，6.99(d，1H)，7.81(d，1H)，7.89(m，3H)，8.09(d，1H)，8.63(s，1H)，8.80(d，1H)，13.00(bs，1H)。
Embodiment 280
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(pyridin-3-yl) thiazole-4-carboxamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (0.060g; 0.215mmol), 2-(pyridin-3-yl) thiazole-4-formic acid (0.044g; 0.215mmol), DIPEA (0.112ml, 0.646mmol), the HOBt hydrate (0.050g, 0.323mmol) and EDCI (0.062g; 0.323mmol) utilize the method for embodiment 274 to prepare, obtain the 0.080g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.20(d，3H)，4.40(m，2H)，4.51(m，1H)，7.02(d，1H)，7.81(d，1H)，7.94(m，3H)，8.33(s，1H)，8.38(d，1H)，8.54(d，1H)，8.71(d，1H)，9.25(bs，1H)。
Embodiment 281
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(pyridin-3-yl)-1H-pyrazole-3-formamide
Title compound is from (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (0.050g; 0.179mmol), 1-(pyridin-3-yl)-1H-pyrazoles-3-formic acid (0.034g; 0.179mmol), DIPEA (0.094ml, 0.538mmol), the HOBt hydrate (0.041g, 0.269mmol) and EDCI (0.052g; 0.269mmol) utilize the method for embodiment 274 to prepare, obtain the 0.079g title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.19(d，3H)，4.38(m，2H)，4.49(m，1H)，6.89(d，1H)，7.01(d，1H)，7.59(m，1H)，7.88(m，3H)，8.30(m，1H)，8.35(d，1H)，8.59(d，1H)，8.65(d，1H)，9.18(d，1H)。
Embodiment 282
3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl) different
Figure BDA0000157427790002131
azoles-5-yl) ethyl)-1H-pyrazoles-5-methane amide
A) (E)-2-chloro-4-((oxyimino) benzonitrile
(2.0g 12.08mmol) is dissolved in exsiccant THF (30ml) with 2-chloro-4-formyl radical benzonitrile.With pyridine (2.9ml, 36.2mmol) and hydroxy amine hydrochloric acid salt (1.68g 24.16mmol) joins in the solution.With mixture heating up to 70 ℃ and stirred 4 hours.With THF evaporation and adding frozen water (50ml).Mixture was stirred 1 hour, throw out is leached and with twice of cold water washing.After 35 ℃ of following dried overnight, obtain (2.04g) title compound. 1H-NMR(400MHz；d6-DMSO)：7.75(dd，1H)，7.90(d，1H)，7.99(d，1H)，8.23(s，1H)，11.93(s，1H)。
B) (Z)-3-chloro-4-cyanic acid-N-hydroxyl benzimidoyl chlorine
((2.04g 11.30mmol) is dissolved in DMF (20ml) and be cooled to 0 ℃ to (oxyimino) benzonitrile with (E)-2-chloro-4-.(1.66g 12.43mmol) and with mixture is warming up to room temperature to add N-neoprene imide.Reaction mixture was at room temperature stirred 2 hours and poured in the frozen water.Filtering product also, drying obtains the 2.26g title compound. 1H-NMR(400MHz；d6-DMSO)：δ7.92(dd，1H)，8.03(d，1H)，8.08(d，1H)，13.06(s，1H)。
C) (2-(3-(3-chloro-4-cyano-phenyl) different
Figure BDA0000157427790002132
azoles-5-yl) ethyl) t-butyl carbamate
(0.7g 4.14mmol) is dissolved in toluene (20ml) and also at room temperature adds triethylamine (0.87ml) with fourth-3-alkynes-1-aminocarbamic acid tert-butyl ester.(0.98g, DMF 4.55mmol) (2ml) solution joins in the reaction mixture with (Z)-3-chloro-4-cyanic acid-N-hydroxyl benzimidoyl chlorine.After at room temperature 1 hour reaction mixture was heated 2 hours down at 40 ℃.White depositions is filtered and will be filtrated with 1MHCl, water and brine wash.Use anhydrous Na 2SO 4Drying is filtered and evaporation.Crude product is passed through purification by flash chromatography (heptane-EtOAc 2: 1).Divide merging and evaporation to obtain title compound (0.78g) the product level. 1H-NMR(400MHz；d6-DMSO)：δ1.35(s，9H)，2.95(t，2H)，3.30(m，2H，)，7.04(m，2H)，8.00(d，1H)，8.12(d，1H)，8.18(s，1H)。
D) 4-(5-(2-amino-ethyl) different
Figure BDA0000157427790002141
azoles-3-yl)-2-benzyl chloride nitrile hydrochloride
(078g 2.24mmol) at room temperature stirred 2 hours with 13w% ETHYLE ACETATE HCl solution (20ml) with (2-(3-(3-chloro-4-cyano-phenyl) different azoles-5-yl) ethyl) t-butyl carbamate.Mixture is filtered and throw out is washed with EtOAc, 30 ℃ of following drying under vacuum overnight.Obtain title compound 0.53g. 1H-NMR(400MHz；d6-DMSO)：δ3.21(m，4H)，7.22(s，1H)，8.02(d，1H)，8.14(d，1H)，8.20(s，1H)，8.27(bs，3H)。
E) 3-ethanoyl-N-(2-(3-(3-chloro-4-cyano-phenyl) different
Figure BDA0000157427790002143
azoles-5-yl) ethyl)-1H-pyrazoles-5-methane amide
Title compound is from 4-(5-(2-amino-ethyl) different
Figure BDA0000157427790002144
azoles-3-yl)-2-benzyl chloride nitrile hydrochloride (0.080g; 0.282mmol), 3-ethanoyl-1H-pyrazoles-5-formic acid (0.043g; 0.282mmol), DIPEA (0.196ml; 1.126mmol l), HOBt hydrate (0.065g; 0.422mmol) and EDCI (0.081g; 0.422mmol) utilize the method for embodiment 274 to prepare, through obtaining the 0.013g title compound behind the preparation HPLC purifying. 1H-NMR(400MHz；d6-DMSO)：δ2.53(s，3H)，3.20(t，2H)，3.83(m，2H)，6.54(s，1H)，7.33(bs，1H)，7.63(bs，1H)，7.79(m，1H)，7.97(bs，1H)。
Embodiment 283
N-(2-(3-(3-chloro-4-cyano-phenyl) different
Figure BDA0000157427790002145
azoles-5-yl) ethyl)-5-(pyridin-3-yl)-1H-pyrazole-3-formamide
Title compound is from 4-(5-(2-amino-ethyl) different
Figure BDA0000157427790002146
azoles-3-yl)-2-benzyl chloride nitrile hydrochloride (0.080g; 0.282mmol), 5-(pyridin-3-yl)-1H-pyrazoles-3-formic acid (0.053g; 0.282mmol), DIPEA (0.196ml; 1.126mmol l), HOBt hydrate (0.065g; 0.422mmol) and EDCI (0.081g 0.422mmol) utilizes the method preparation of embodiment 274.Title compound is changed into HCl salt in 2 hours through handling with the 1MHCl diethyl ether solution, obtain the 0.056g title compound. 1H-NMR(400MHz；d6-DMSO)：3.15(t，2H)，3.66(m，2H)，7.16(s，1H)，7.42(bs，1H)，7.90(m，1H)，8.02(d，1H)，8.13(d，1H)，8.21(s，1H)，8.63(d，1H)，8.75(d，1H)，8.83(bs，1H)，9.19(s，1H)。
Embodiment 284
Pyridine-2-formic acid (E)-and 2-[5-(3, the 4-dichlorophenyl) furans-2-yl] vinyl } acid amides
A) 2-bromo-5-((E)-2-nitroethylene base) furans
With 5-bromo-2 furan carboxyaldehyde (5.26g, 0.0300mol) and Nitromethane 99Min. (2.2ml, 2.43g, methyl alcohol 0.0300mol) (40ml) solution join NaOH under 0 ℃ (1.20g is in water 0.0300mol) (40ml) solution.The mixture that forms was stirred 2 hours down at 0 ℃, use frozen water (25ml) dilution then.The solution that forms is slowly joined under＜0 ℃ among the 10%HCl (10ml).Isolated throw out is leached, and water and heptane wash and drying obtain title compound. 1H?NMR(400MHz，DMSO-d 6)：6.90(1H，d)，7.30(1H，d)，7.77(1H，d)，7.96(1H，d)。
B) 2-bromo-5-(2-nitro-1-thiophenyl ethyl) furans
With 2-bromo-5-((E)-2-nitroethylene base) furans (1.50g; 0.006880mol), thiophenol (0.91ml; 0.99g; 0.008945mol) and N-isopropylcyclohexyl-amine (dry methylene chloride 0.0006017mol) (150ml) solution at room temperature stirred under nitrogen 4.5 hours for 0.1ml, 0.085g.With the solution with water washing, use Na then 2SO 4Dry also evaporation.Product is kept in the refrigerator. 1H?NMR(400MHz，DMSO-d 6)：4.94-5.01(1H，m)，5.11-5.17(2H，m)，6.37(1H，d)，6.49(1H，d)，7.38(5H，m)。
C) 2-(5-bromine furans-2-yl)-2-thiophenyl ethylamine
With zinc powder (0.80g, 0.01224mol) the 2-bromo-5-that under nitrogen, joins the mixture that is dissolved in glacial acetic acid (24ml) and concentrated hydrochloric acid (2.4ml) under 80 ℃ (2-nitro-1-thiophenyl ethyl) furans (0.60g, 0.001828mol) in.Mixture was heated 2.5 hours down at 80 ℃.Add 0.40g (0.00612mol) zinc powder then and with mixture heating up 1 hour.With reaction mixture cooling and adding 36ml water.PH is adjusted to 9 with 2.5M NaOH.Product is used ethyl acetate extraction.Organic phase is used water washing, dry and evaporation. 1H NMR (400MHz, DMSO-d 6): 2.87 (1H, distored dd), 2.97 (1H, distored dd), 4.41 (1H, t), 6.21 (1H, d), 6.45 (1H, d), 7.31 (5H, m).
D) pyridine-2-formic acid [2-(5-bromine furans-2-yl)-2-thiophenyl ethyl] acid amides
With 2-(5-bromine furans-2-yl)-2-thiophenyl ethylamine (0.28g, 0.0009389mol), (0.12g 0.001005mol) stirs in exsiccant THF (10ml) with EDCI the 2-VPP.Evaporating solvent after raw material disappears.Add chloroform then and solution is used 1M Na 2CO 3And water washing, use Na 2SO 4Dry also evaporation.Through purification by flash chromatography, utilize heptane-EtOAc crude product as gradient elution agent (85: 15-70: 30). 1H?NMR(400MHz，DMSO-d 6)：3.75-3.80(2H，m)，4.78-4.84(1H，m)，6.33-6.37(2H，m)，6.44(1H，d)，7.26-7.40(4H，m)，7.59-7.62(1H，m)，7.97-8.04(2H，m)，8.62-8.64(1H，m)，9.08(1H，m)。
E) pyridine-2-formic acid [2-benzenesulfinyl-2-(5-bromine furans-2-yl) ethyl] acid amides
(57mg, less water solution 0.2677mmol) join pyridine-2-formic acid [2-(5-bromine furans-2-yl)-2-thiophenyl ethyl] acid amides, and (90mg is in methyl alcohol 0.2231mmol) (13ml) solution with sodium periodate.Reflux to add 57mg (0.2677mmol) sodium periodate after 4 hours and continue and refluxed 4.5 hours.Add entry (30ml) and product is extracted with EtOAc.Organic phase is used water washing, use Na 2SO 4Dry also evaporation.Crude product directly is used for next step.
F) pyridine-2-formic acid [(E)-2-(5-bromine furans-2-yl) vinyl] acid amides
With pyridine-2-formic acid [2-benzenesulfinyl-2-(5-bromine furans-2-yl) ethyl] acid amides (0.11g, 0.2623m mol) and Na 2CO 3(0.03g, toluene mixture 0.2623mmol) refluxed in nitrogen 2 hours.Toluene solution with 1M NaOH (25ml) washing, is used Na 2SO 4Dry also evaporation.Through purification by flash chromatography, utilize heptane-EtOAc crude product as gradient elution agent (90: 10-80: 20).E isomer is used for next step.
G) pyridine-2-formic acid { (E)-2-[5-(3, the 4-dichlorophenyl) furans-2-yl] vinyl } acid amides
(0.014g 0.0477mmol) is dissolved in 1 to acid amides, 4-dioxan (4.2ml) with pyridine-2-formic acid [(E)-2-(5-bromine furans-2-yl) vinyl] in the microwave reaction bottle.Add 3,4-dichlorophenyl boric acid (0.0091g, 0.0477mmol), three alkali formula potassiumphosphates (0.020g, 0.0954mmol), 0.7ml water and tetrakis triphenylphosphine palladium (0) (0.005g, 0.0047mmol).After removing oxygen reaction mixture was shone 10 minutes down at 160 ℃.Add entry (7ml) then.Product is extracted (2x15ml) with EtOAc.Organic phase is used water washing, use Na 2SO 4Dry also evaporation.Crude product is passed through purification by flash chromatography (eluent: heptane-EtOAc 7: 3). 1H NMR (400MHz, CDCl 3): 6.26 (1H, d), 6.29 (1H, d), 6.66 (1H, d), 7.45 (1H, distored d), 7.48-7.52 (2H, m), 7.69-7.76 (2H, m), 7.91 (1H, td), 8.27 (1H, d), 8.61 (1H, dd), 9.88 (1H, d).
Embodiment 285
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-sec.-propyl-1; 2,4-
Figure BDA0000157427790002171
diazole-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (0.33g; 1.28mmol), 3-sec.-propyl-1; 2; 4-
Figure BDA0000157427790002172
diazole-5-formic acid (0.2g, 1.28mmol), HOBt (0.26g, 1.92mmol), DIPEA (0.7mL; 3.84mmol) and EDCI (0.37g 1.92mmol) prepares as solvent as prepared using DMF (10mL).Yield 0.197g. 1H?NMR(400MHz；MeOD)：δ1.24(d，3H)，1.33(d，6H)，3.15(m，1H)，4.38(m，2H)，4.57(m，1H)，6.78(d，1H)，7.71(d，1H)，7.77(m，1H)，7.87(dd，1H)，8.02(dd，1H)。
Embodiment 286
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-methyl isophthalic acid-(3-oxo butyl)-1H-imidazoles-4-methane amide
A) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
Title compound utilizes the method for embodiment 34 (d) with 2-methyl isophthalic acid H-imidazoles-4-formic acid (0.497g; 3.94mmol) and embodiment 116 (f) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(1.2g 4.31mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through purification by flash chromatography.Yield 10.21%. 1H-NMR(400MHz；DMSO-d6)：δ1.07(d，3H)，2.31(s，3H)，4.25-4.46(m，3H)，7.02(d，1H)，7.42(d，1H)，7.86(d，1H)，7.93(dd，1H)，8.00(s，1H)，8.07(d，1H)，12.11(s，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-methyl isophthalic acid-(3-oxo butyl)-1H-imidazoles-4-methane amide
With 1-Methylimidazole (1.030 μ l), 0.013mmol) and DMSO (3ml) join in the flask.Add (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-the yl)-2-methyl isophthalic acid H-imidazoles-4-methane amide be dissolved in 3ml DMSO (100mg, 0.259mmol).(0.065ml 0.776mmol) and with the mixture that forms stirred 2.5 hours down at 70 ℃ to add methyl vinyl ketone at last.Mixture is at room temperature stirred a whole night, and once more rise to 70 ℃ and stir 3.5 hour with temperature the next morning.Add 0.195ml methyl vinyl ketone and 16.48 μ l1-Methylimidazoles altogether and mixture was stirred 3 days down at 70 ℃ in the final section of reaction.10ml water is poured in the mixture and the white solution that forms is used ethyl acetate extraction.The ETHYLE ACETATE that merges is dry mutually, filter and evaporation.Product is passed through purification by flash chromatography also with ACN/ water recrystallization.Yield 42.3%. 1H-NMR(400MHz；DMSO-d6)：δ1.05(d，3H)，2.09(s，3H)，2.35(s，3H)，2.97(t，2H)，4.04(t，2H)，4.23-4.45(m，3H)，7.01(d，1H)，7.48(s，1H)，7.85(d，1H)，7.93(dd，1H)，8.00(s，1H)，8.05(d，1H)。
Embodiment 287
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(3-hydroxy-3-methyl butyl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
Et with the 3M methyl-magnesium-bromide 2(0.128ml 0.383mmol) joins in the flask and is heated to 30 ℃ with exsiccant THF (1ml) O solution.Add very lentamente the embodiment 286 (b) be dissolved in THF (5ml) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-methyl isophthalic acid-(3-oxo butyl)-1H-imidazoles-4-methane amide (35mg, 0.077mmol).Reaction mixture is heated to 45 ℃ and stirred 5 hours.Add the EtO of a collection of 3M methyl-magnesium-bromide 2(0.128ml is 0.383mmol) and with mixture stirred overnight at room temperature for solution.Reaction mixture poured in the 10ml saturated ammonium chloride in second day, evaporation THF also uses ethyl acetate extraction with remaining water.ETHYLE ACETATE is merged mutually dry and evaporation.Product is passed through purification by flash chromatography.Yield 19.32%. 1H-NMR(400MHz；DMSO-d6)：δ1.06(d，3H)，1.12(s，6H)，1.69-1.77(m，2H)，2.34(s，3H)，3.92-3.98(m，2H)，4.25-4.46(m，4H)，7.01(d，1H)，7.50(s，1H)，7.85(d，1H)，7.92(dd，1H)，8.00(s，1H)，8.03(d，1H)。
Embodiment 288
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyridine-2-carboxamide
A) imidazo [1,2-a] pyridine-2-formic acid
To contain imidazo [1,2-a] pyridine-2-ethyl formate (1g, 5.26mmol), add Lithium Hydroxide MonoHydrate (0.378g, 15.77mmol) and at room temperature stirred overnight in the mixture of THF (5ml) and water (5ml).The pH of reaction mixture is adjusted to 2 and evaporate THF with 2M HCl.With remaining water with ethyl acetate extraction and the ETHYLE ACETATE that merges is dry mutually.Product has been precipitated into aqueous phase.Vaporize water is also used recrystallizing methanol with remaining solid.Product is used for next step with the form of salt. 1H-NMR(400MHz；DMSO-d6)：δ7.23-7.26(m，1H)，7.63-7.70(m，1H)，7.76(dd，1H)，8.72(s，1H)，8.73-8.77(m，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyridine-2-carboxamide
The method that title compound utilizes embodiment 34 (d) with imidazo [1,2-a] pyridine-2-formic acid (0.853g, 5.26mmol) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(1.0g 3.59mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is also used the acetonitrile/water recrystallization through purification by flash chromatography.Yield 39.0%. 1H-NMR(400MHz；DMSO-d6)：δ1.13(d，3H)，4.35(dd，1H)，4.43(dd，1H)，4.47-4.57(m，1H)，6.96-7.01(m，1H)，7.02(d，1H)，7.34-7.40(m，1H)，7.60(dd，1H)，7.89(d，1H)，7.93(dd，1H)，7.97(s，1H)，8.32(d，1H)，8.55-8.58(m，1H)，8.61(d，1H)。
Embodiment 289
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-p-methoxy-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790002201
azoles-3-methane amide
A) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790002202
azoles-3-methane amide
Title compound utilizes 5-(2-hydroxy propane-2-yl) different azoles-3-formic acid (0.096g of the method for embodiment 34 (d) with embodiment 77 (a); 0.560mmol) and embodiment 116 (f) (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.12g 0.431mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through with ethyl alcohol recrystallization purifying.Yield 36.0%. 1H-NMR(400MHz；DMSO-d6)：δ1.16(d，3H)，1.47(s，6H)，4.32(d，2H)，4.39-4.51(m，1H)，5.67(s，1H)，6.49(s，1H)，7.01(d，1H)，7.85(d，1H)，7.87(dd，1H)，7.99(s，1H)，8.74(d，1H)。
B) (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-p-methoxy-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790002204
azoles-3-methane amide
With (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790002205
azoles-3-methane amide (50mg; 0.116mmol), the dry methyl alcohol of 5ml and cesium carbonate (75mg; 0.232mmol) mixture under agitation reacted 6 days; By day temperature is remained on 60 ℃, at night temperature is remained on room temperature.With the mixture evaporation, be dissolved in DCM, the water extraction is also dry.Product is passed through purification by flash chromatography.Yield 60.3%. 1H-NMR(400MHz；DMSO-d6)：δ1.15(d，3H)，1.46(s，6H)，4.01(s，3H)，4.32(d，2H)，4.40-4.51(m，1H)，5.68(s，1H)，6.49(s，1H)，7.00(d，1H)，7.54(d，1H)，7.67(d，1H)，7.83(d，1H)，8.75(d，1H)。
Embodiment 290
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(pyridin-3-yl)-1H-imidazoles-4-methane amide
With 3-pyridine boric acid 1; Ammediol ester (43.7mg; 0.268mmol), (S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-imidazoles-4-methane amide (50mg; 0.134mmol), anhydrous cupric acetate (II) (36.5mg, 0.201mmol), pyridine (0.022ml, 0.268mmol) and DCM (1ml) join in the flask and at room temperature stirred 47 hours.Reaction mixture is used ethyl acetate extraction, and drying is filtered and evaporation.Product is passed through purified.Yield 16.57%. 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，4.28(dd，1H)，4.47(dd，1H)，4.57-4.67(m，1H)，6.64(d，1H)，7.48-7.55(m，2H)，7.74-7.78(m，1H)，7.81(d，1H)，7.88(d，1H)，7.91-7.94(m，2H)，8.27(d，1H)，8.72(d，1H)，8.79(d，1H)。
Embodiment 291
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-benzo [d] imidazoles-2-methane amide
Title compound utilizes the method for embodiment 34 (d) with 1H-benzo [d] imidazoles-2-formic acid (100mg; 0.617mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (161mg; 0.617mmol) as prepared using N, dinethylformamide prepares as solvent.Product is also used the chloroform recrystallization through purification by flash chromatography.Yield 20.03%. 1H-NMR(400MHz；CDCl 3)：δ1.33(d，3H)，4.32(dd，1H)，4.47(dd，1H)，4.64-4.75(m，1H)，6.59(d，1H)，7.34-7.41(m，2H)，7.50(d，1H)，7.52-7.56(m，1H)，7.62(d，1H)，7.81-7.87(m，2H)，8.00(d，1H)，8.42(d，1H)，10.87(s，1H)。
Embodiment 292
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3,3 '-dipyridyl-6-methane amide
Title compound utilizes the method for embodiment 34 (d) with 5-(pyridin-3-yl) VPP (130mg; 0.549mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (150mg; 0.577mmol) as prepared using N, dinethylformamide prepares as solvent.Product is passed through purification by flash chromatography.Yield 45.2%. 1H-NMR(400MHz；DMSO-d6)：δ1.18(d，3H)，4.38(dd，1H)，4.46(dd，1H)，4.49-4.59(m，1H)，6.96(d，1H)，7.59(q，1H)，7.87(d，1H)，7.97(dd，1H)，8.01(d，1H)，8.06-8.12(m，2H)，8.21-8.26(m，1H)，8.35(dd，1H)，8.69(dd，1H)，9.01-9.07(m，2H)，9.14(d，1H)。
Embodiment 293
Acetate 1-(5-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-pyrazole-3-yl) ethyl ester
To contain N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide (400mg, 1.003mmol) and DMAP (12.25mg, flask 0.100mmol) places under the nitrogen atmosphere.Add pyridine (10ml), with reaction mixture be cooled to 0 ℃ and drip diacetyl oxide (0.099ml, 108mg).Mixture is warming up to room temperature and stirred overnight.Second day with mixture evaporation and pass through purification by flash chromatography.Yield 58.9%. 1H-NMR(400MHz；DMSO-d6)：δ1.15(d，3H)，1.51(d，3H)，2.02(s，3H)，4.25-4.37(m，2H)，4.39-4.49(m，1H)，5.88(q，1H)，6.64(s，1H)，6.90(dd，1H)，7.80(dd，1H)，7.91-7.96(m，2H)，8.04-8.07(m，1H)，8.15(s，1H)，13.24(s，1H)。
Embodiment 294
Acetate 1-(1-ethanoyl-3-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-pyrazoles-5-yl) ethyl ester
Title compound obtains from embodiment 293 described Reaction Separation with the form of by product.Yield 1.920%. 1H-NMR(400MHz；DMSO-d6)：δ1.17(d，3H)，1.47(dd，3H)，2.04(s，3H)，2.72(s，3H)，4.29-4.41(m，2H)，4.42-4.53(m，1H)，6.28(q，1H)，6.85(d，1H)，6.95(d，1H)，7.83-7.85(m，1H)，7.9-7.94(m，1H)，7.97(dd，1H)，8.06(s，1H)，8.40(d，1H)。
Embodiment 295
(S)-2-ethanoyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
The method that title compound utilizes embodiment 34 (d) with 2-acetylthiazole-4-formic acid (1.444g, 8.44mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(2.0g 7.67mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through with ethyl alcohol recrystallization purifying.Yield 93%. 1H-NMR(400MHz；DMSO-d6)：δ1.20(d，3H)，2.70(s，3H)，4.37(dd，1H)，4.44(dd，1H)，4.48-4.56(m，1H)，6.96(d，1H)，7.87(d，1H)，7.92(dd，1H)，7.97(dd，1H)，8.04(d，1H)，8.48(d，1H)，8.61(s，1H)。
Embodiment 296
Acetate 1-(4-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) ethyl ester
A) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide
To containing (S)-2-ethanoyl-N-(1-(3-(3-chloro-4-the cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide (1g that is dissolved in ethanol (10ml); 2.416mmol) flask under nitrogen, be divided into aliquot add Peng Qinghuana (0.137g, 3.62mmol).With following mixture stirred overnight at room temperature.Drip water (1ml) the next morning, the pH of mixture is adjusted to below 7 and with mixture with 1M HCl evaporates.Add 30ml ETHYLE ACETATE and also stirred 30 minutes, filter, will filtrate and evaporate and 40 ℃ of following vacuum-dryings.With product through purifying obtains 41.6% title compound with twice of diethyl ether/ethyl alcohol recrystallization. 1H-NMR(400MHz；DMSO-d6)：δ1.10-1.16(m，3H)，1.44-1.48(m，3H)，4.29-4.52(m，3H)，4.94-4.02(m，3H)，6.22-6.26(m，1H)，6.95-6.99(m，1H)，7.83-7.88(m，1H)，7.93-8.00(m，2H)，8.07-8.10(m，1H)，8.11(d，1H)，8.33-4.39(m，1H)。
B) acetate 1-(4-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl) thiazol-2-yl) ethyl ester
With N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyl-ethyl) thiazole-4-carboxamide (250mg; 0.601mmol), 4-dimethylamino-pyridine (7.34mg, 0.060mmol) and pyridine (3ml) join in the flask and and be cooled to 0 ℃ mixture.(0.063ml 0.661mmol) and with mixture under agitation is warming up to room temperature to drip diacetyl oxide.The reaction solution reaction is spent the night.(10 μ l 0.106mmol) and with reaction solution at room temperature continued to stir 1 hour to add diacetyl oxide the next morning.With the mixture evaporation and 40 ℃ of following drying under vacuum overnight.With product through purifying obtains 24.09% end product with ethanol/twice in heptane recrystallization. 1H-NMR(400MHz；DMSO-d6)：δ1.14(d，3H)，1.62(dd，3H)，2.11(s，3H)，4.29-4.53(m，3H)，6.02-6.10(m，1H)，6.94-6.98(m，1H)，7.84-7.87(m，1H)，7.92-8.00(m，2H)，8.07(d，1H)，8.22(d，1H)，8.38-4.49(m，1H)。
Embodiment 297
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide
Following method can prepare the optically pure 1-hydroxyl propionic acid amide of pure diastereomer form.Described with the method for racemize raw material at this as raw material.
A) 2-(t-butyldiphenylsilyl oxygen base) propionic acid amide
With 2-hydroxyl-propionic acid amide (227mg; 2.55mmol), DMF (2ml), tert-butyl diphenyl chlorosilane (1.0ml; 1057mg), (266mg, 3.91mmol) (93mg 0.764mmol) stirred weekend to imidazoles under nitrogen atmosphere with the 4-dimethylamino-pyridine that is dissolved in DMF (2ml).Later temperature is risen to 90 ℃ weekend and also continue reaction 4 hours.Then with the mixture evaporation and with the extraction of DCM/ water, with the organic phase evaporation that merges.Product is passed through purified. 1H-NMR(400MHz；DMSO-d6)：δ1.04(d，9H)，1.12(d，3H)，4.00(q，1H)，7.04(bs，1H)，7.24(bs，1H)，7.40-7.51(m，6H)，7.58-7.66(m，4H)。
B) 2-(t-butyldiphenylsilyl oxygen base) propane thioamides
To contain 2,4-two (4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphorus heterocycle butane-2, (387mg, flask 0.957mmol) places under the nitrogen atmosphere 4-disulphide.(622mg 1.899mmol), rises to 60 ℃ and with mixture reaction 3 hours with temperature to add 2-(the t-butyldiphenylsilyl oxygen base) propionic acid amide be dissolved in dry THF (10ml).Evaporating solvent also extracts product with DCM/ water.Product directly is used for next step without being further purified.LC-MS：[M+1]＝344.56。
C) 2-(1-(t-butyldiphenylsilyl oxygen base) ethyl) thiazole-4-formic acid
(317mg, flask 1.901mmol) places under the nitrogen atmosphere will to contain the acid of 3-martonite.(653mg 1.901mmol) is dissolved in exsiccant THF (8ml) and also adds through barrier film with 2-(t-butyldiphenylsilyl oxygen base) propane thioamides.Mixture was refluxed 2 hours, be cooled to room temperature then.Evaporating solvent is also with the extraction of DCM/ water, with the organic phase evaporation that merges. 1H-NMR(400MHz；DMSO-d6)：δ1.07(s，9H)，1.35(d，3H)，5.14(q，1H)，7.39-7.54(m，2H)，7.57-7.61(m，2H)，7.26-7.69(m，2H)，8.38(s，1H)。
D) 2-(1-(t-butyldiphenylsilyl oxygen base) ethyl)-N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide
Title compound utilizes the method for embodiment 34 (d) with 2-(1-(t-butyldiphenylsilyl oxygen base) ethyl) thiazole-4-formic acid (326mg; 0.792mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(105mg 0.403mmol) prepares as raw material 2-benzyl chloride nitrile 4-.After the extraction,, estimate the enough pure next step that can be used for of product based on the LC-MS data.LC-MS：[M+1]＝655.30。
E) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(1-hydroxyethyl) thiazole-4-carboxamide
To be dissolved in 2-(1-(t-butyldiphenylsilyl oxygen base) ethyl)-N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) thiazole-4-carboxamide (264mg of THF (20ml); 0.403mmol) and the THF solution of 1.0M tetrabutyl ammonium fluoride (0.41ml 0.410mmol) joins in the flask and stirred overnight at room temperature.React after 1 hour the THF solution that adds the 1.0M tetrabutyl ammonium fluoride (0.41ml, 0.410mmol).Crude product is also extracted with DCM/ water through evaporation drying.Organic phase is separated and evaporation with phase separator.Product is also used the ethyl acetate/heptane recrystallization through purification by flash chromatography. 1H-NMR(400MHz；DMSO-d6)：δ1.10-1.15(m，3H)，1.46(t，3H)，4.29-4.52(m，3H)，4.93-5.01(m，1H)，6.24(s，1H)，6.94-6.98(m，1H)，7.83-7.87(m，1H)，7.92-8.00(m，2H)，8.08(s，1H)，8.10(d，1H)，8.33-8.39(m，1H)。
Embodiment 298
(S)-3-ethanoyl-N-(1-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 5-(3, the 4-dichlorophenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles
(6.16g, 22.13mmol) with 4-bromo-1, (2.84ml 22.13mmol) is dissolved in DMF (20ml) to 2-two chloro-benzene under nitrogen with 1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-boric acid pinacol ester.(22.13ml, (0.777g 1.107mmol) and with the mixture that forms stirred 3 hours down at 50 ℃ 44.3mmol) to add two (triphenylphosphine)-Palladous chlorides (I1) together with yellow soda ash.With the DMF evaporation, add entry (15ml) and use ethyl acetate extraction.The organic phase that merges is used Na 2SO 4Drying is filtered and 40 ℃ of following vacuum-dryings.With product through with diethyl ether and diethyl ether/heptane recrystallization and purifying. 1H-NMR(400MHz；DMSO-d6)：δ1.50-1.69(m，3H)，1.77-1.84(m，1H)，1.91-2.00(m，1H)，2.31-2.44(m，1H)，3.54-3.62(m，1H)，3.96-4.02(m，1H)，5.23(dd，1H)，6.89(d，1H)，7.53(dd，1H)，7.60(d，1H)，7.77-7.82(m，2H)。
B) 5-(3, the 4-dichlorophenyl)-1H-pyrazoles
(2.840g 9.56mmol) (10ml) joins in the flask with the EtOH solution (1.9mmol/ml) of 10%HCl and at room temperature stirred weekend with 5-(3, the 4-dichlorophenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles.Then mixture is evaporated.Add entry (45ml) and mixture is used saturated NaHCO 3Neutralization.Mixture is used Na with ethyl acetate extraction and with the organic phase that merges 2SO 4Dry.Leach siccative, with the mixture evaporation that obtains and 40 ℃ of following vacuum-dryings.Product itself can use without being further purified. 1H-NMR(400MHz；DMSO-d6)：δ6.83-6.86(m，1H)，7.65(d，1H)，7.72-7.86(m，2H)，8.05(d，1H)，13.06(s，1H)。
C) (S)-1-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) propane-2-amine
To containing 5-(3; The 4-dichlorophenyl)-1H-pyrazoles (1.5g; 7.04mmol), (S)-tertiary butyl 1-hydroxy propane-2-aminocarbamic acid ester (1.357g, 7.74mmol) and triphenylphosphine (2.77g adds exsiccant THF (30ml) under nitrogen in flask 10.56mmol).After stirring several minutes, (2.77ml 14.08mmol), utilizes the ice bath cooling to raise to prevent temperature simultaneously to drip DIAD through barrier film.With the mixture that forms stirred overnight at room temperature.Mixture is evaporated.Remove the Boc-protection through adding ethanol (7ml), 10%HCl/EtOH (50ml), dense HCl (5ml), mixture was stirred weekend.With the mixture evaporation, extract with DCM/ water.With the pH of water with 2M NaOH be adjusted to～12 and extract with DCM once more.The organic phase that merges is used Na 2SO 4Drying is filtered and evaporation. 1H-NMR(400MHz；DMSO-d6)：δ1.00(d，3H)，4.70-4.87(m，3H)，6.84(d，1H)，7.65(d，1H)，7.76-7.84(m，2H)，8.02(d，1H)。
D) (S)-3-ethanoyl-N-(1-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
The method that title compound utilizes embodiment 34 (d) with 3-ethanoyl-1H-pyrazoles-5-formic acid (71.9mg, 0.466mmol) with (S)-(126mg 0.466mmol) prepares as raw material propane-2-amine 1-(3-(3, the 4-dichlorophenyl)-1H-pyrazol-1-yl).Product is passed through with the acetonitrile recrystallization purifying.Yield 12.61%. 1H-NMR (400MHz; DMSO-d6): δ 1.05-1.25 (m, 3H), 4.18-4.53 (m, 3H), 6.79 (s, 1H), 7.31 (s, 1H), 7.57-7.85 (m, 3H), 7.89-7.98 (m, 1H), 8.39-8.54 (m, 1H), 14.05&14.12 (2 * wide s, 1H).
Embodiment 299
(S, E/Z)-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-(oxyimino) ethyl)-1H-pyrazoles-5-methane amide
To (the S)-3-ethanoyl-N-that contains the embodiment 78 that is dissolved in ethanol (3ml) and THF (1ml) (1-(3-(4-cyanic acid-3; The 5-difluorophenyl)-and the 1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide (50.0mg; 0.126mmol) flask in add oxyamine HCl (10.47mg; 0.151mmol) and anhydrous sodium acetate (12.36mg, 0.151mmol).The mixture that forms was at room temperature stirred 5 hours, add 5 dimethyl amines then.Continue stirred overnight.Second day with the mixture evaporation and with ETHYLE ACETATE/water extraction.The organic phase that merges is used Na 2SO 4Drying is filtered and evaporation.Crude product is spent weekend 40 ℃ of following vacuum-dryings.Product is enough pure, need not to be further purified step.Product obtains with the form of the E/Z isomer mixture of oxime.Yield 82%. 1H-NMR(400MHz；DMSO-d6)：δ1.13-1.19(m，3H)，2.11(s，2H，E/Z)，2.16(s，1H，E/Z)，4.26-4.37(m，2H)，4.40-4.51(m，1H)，6.97(d，1H)，7.71(s，1H)，7.74(s，1H)，7.82-7.84(m，1H)，8.26(bs，1H)，11.07(bs，～0.5H)，11.27(bs，～0.5H)，13.48(bs，1H)。
Embodiment 300
N-((S)-1-(4-chloro-3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
To containing the Sodium Borohydride (0.022g that is dissolved in ethanol (1ml); 0.580mmol) 0 ℃ of solution in slowly add (S)-3-ethanoyl-N-(1-(4-chloro-3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide of being dissolved in 2ml alcoholic acid embodiment 224 (0.125g, 0.290mmol).Mixture is stirred several minutes down at 0 ℃, then mixture is warming up to room temperature and continues and stirred 4.5 hours.Slowly add several dripping.PH is adjusted to below 4 with 2M HCl.Evaporating solvent also extracts resistates with DCM/ water.Organic phase is separated and evaporation with phase separator.Product is passed through with ethyl alcohol recrystallization purifying.Yield 51.0%. 1H-NMR(400MHz；DMSO-d6)：δ1.14(d，3H)，1.38(d，3H)，4.23-4.37(m，2H)，4.40-4.50(m，1H)，4.75-4.83(m，1H)，5.40(d，1H)，6.40(s，1H)，8.00(dd，1H)，8.04(dd，1H)，8.05-8.14(m，3H)，13.03(s，1H)。
Embodiment 301
(R, E/Z)-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-3-(1-(oxyimino) ethyl)-1H-pyrazoles-5-methane amide
A) (R)-3-ethanoyl-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with 3-ethanoyl-1H-pyrazoles-5-formic acid (0.229g; 1.486mmol) and (R)-4-(1-(1-aminopropane-2-yl)-1H-pyrazole-3-yl)-2; (0.380g 1.449mmol) prepares as raw material 6-difluoro benzonitrile.Product is passed through purification by flash chromatography.Yield 64.4%. 1H-NMR(400MHz；CDCl 3)：δ1.62(d，3H)，2.55(s，3H)，3.74-3.83(m，1H)，3.90-3.98(m，1H)，4.60-4.69(m，1H)，6.59(d，1H)，7.31(bs，1H)，7.51(d，1H)，7.53(s，1H)，7.55(s，1H)，7.60(bs，1H)，10.97(bs，1H)。
B) (R, E/Z)-N-(2-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propyl group)-3-(1-(oxyimino) ethyl)-1H-pyrazoles-5-methane amide
To containing (R)-3-ethanoyl-N-(2-(3-(the 4-cyanic acid-3 that is dissolved in ethanol (3ml); The 5-difluorophenyl)-and the 1H-pyrazol-1-yl) propyl group)-1H-pyrazoles-5-methane amide (50.2mg; 0.126mmol) add hydroxy amine hydrochloric acid salt (10.51mg in the solution; 0.151mmol) and anhydrous sodium acetate (12.40mg, 0.151mmol).After the product that forms at room temperature stirred 5 hours, add 5 dimethyl amines and continue stirred overnight.With the mixture evaporation,, the organic phase that merges is used Na with ETHYLE ACETATE/water extraction 2SO 4Drying is filtered and evaporation.Last product is passed through purification by flash chromatography.Product obtains with the form of the E/Z isomer mixture of oxime.Yield 81%. 1H-NMR(400MHz；DMSO-d6)：δ1.48(d，3H)，2.10(s，2.25H，E/Z)，2.14(s，0.75H，E/Z)，3.56-3.72(m，2H)，4.62-4.76(m，1H)，6.98(d，1H)，7.76(s，1H)，7.79(s，1H)，7.90(d，1H)，8.19(bs，～0.5H)，8.55(bs，～0.5H)，10.98(bs，～0.5H)，11.31(bs，～0.5H)，13.48(s，1H)。
Embodiment 302
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(furans-2-yl)-1H-pyrazoles-5-methane amide
The method that title compound utilizes embodiment 34 (d) with 5-(2-furyl)-2H-pyrazoles-3-formic acid (3.42g, 19.18mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(5g 19.18mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is also used the acetonitrile recrystallization through purification by flash chromatography.Yield 16.97%. 1H-NMR (400MHz; CDCl 3): δ 1.26 (d, 3H), 4.30 (dd, 1H), 4.42 (dd, 1H), 4.53-4.63 (m, 1H), 6.50 (dd, 1H); 6.62 (d, 1H), 6.67 (d, 1H), 6.94 (s, 1H), 7.48 (dd, 1H), 7.53 (d; 1H), 7.68 (d, 1H), 7.73-7.84 (m, 2H), 8.02 (s, 1H), 13.70 (wide s, 1H).
Embodiment 303
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-4-cyanic acid-1H-pyrazol-1-yl) propane-2-yl)-1-methyl isophthalic acid H-imidazoles-4-methane amide
A) 4-(4-bromo-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-benzyl chloride nitrile
With 2-chloro-4-(1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl) benzonitrile (10g, 34.8mmol) and acetonitrile (120ml) join in the flask and and be adjusted to 0 ℃ with ice bath with temperature.(6.80g 38.2mmol), remains on temperature below 5 ℃ simultaneously to divide aliquot to add N-bromo-succinimide.Mixture was at room temperature stirred 3 hours.Add 10%NaHSO 3(100ml) and with mixture stirred 15 minutes.Reaction mixture is extracted with DCM.The organic phase that merges is dry, filter and evaporation.Product is passed through with ethyl alcohol recrystallization purifying.Yield 82%. 1H-NMR(400MHz；DMSO-d6)：δ1.51-1.59(m，2H)，1.62-1.76(m，1H)，1.90-2.00(m，2H)，2.06-2.18(m，1H)，3.62-3.70(m，1H)，3.91-3.98(m，1H)，5.49(dd，1H)，8.02(dd，1H)，8.09(d，1H)，8.12(d，1H)，8.38(s，1H)。
B) 5-(3-chloro-4-cyano-phenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-4-formonitrile HCN
With 4-(4-bromo-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-5-yl)-2-benzyl chloride nitrile (3g, 8.18mmol), (0.733g, 8.18mmol) and N, dinethylformamide (15ml) joins in the microwave reactor test tube cuprous cyanide (I).Mixture was heated 5 hours down at 190 ℃.Through mixture being poured in the 200ml12% ammonia soln into termination reaction and being stirred 30 minutes.Throw out is filtered, with water washing and 40 ℃ of following vacuum-dryings.Product promptly can be used for next step without being further purified.LC-MS：[M+1]＝313.75。
C) 5-(3-chloro-4-cyano-phenyl)-1H-pyrazoles-4-formonitrile HCN
(2.686g adds ethanol (50ml) solution of 10%HCl and with the mixture stirred overnight that forms in solution 8.59mmol) to containing 5-(3-chloro-4-cyano-phenyl)-1-(tetrahydrochysene-2H-pyrans-2-yl)-1H-pyrazoles-4-formonitrile HCN of being dissolved in ethanol (25ml).Crude product is extracted with DCM/ water.The pH of water is adjusted to 12 through adding 2M NaOH.Water is extracted with DCM once more.The organic phase that merges is used Na 2SO 4Drying is filtered and evaporation.Product is passed through purification by flash chromatography. 1H-NMR(400MHz；DMSO-d6)：δ8.00-8.05(m，1H)，8.13-8.19(m，2H)，8.75(s，1H)，14.24(s，1H)。
D) (S)-1-(2-aminopropyl)-3-(3-chloro-4-cyano-phenyl)-1H-pyrazoles-4-formonitrile HCN
To be dissolved in 5-(3-chloro-4-cyano-phenyl)-1H-pyrazoles-4-formonitrile HCN (0.9g of exsiccant THF (15ml); 3.94mmol), (S)-tertiary butyl 1-hydroxy propane-2-aminocarbamic acid ester (0.690g; 3.94mmol) and (1.549g 5.90mmol) joins in the flask and with ice bath and is cooled to 0 ℃ to be dissolved in the triphenylphosphine of exsiccant THF (15ml).(1.360g 5.90mmol) and stirred 10 minutes, remains on 0 ℃ with temperature simultaneously slowly to add tert-butyl azodicarboxylate.Temperature is risen to room temperature and with the mixture stirred overnight.Second day with mixture evaporation and with midbody through add 10%HCl/EtOH solution (40ml) also at room temperature stirred overnight come deprotection.Mixture is evaporated once more and resistates is extracted with DCM/ water.The pH of water is adjusted to 12 and extract with DCM once more through adding 2M NaOH.Organic phase is separated and evaporation with phase separator.Product promptly can be used for next step without being further purified. 1H-NMR(400MHz；DMSO-d6)：δ1.14(d，3H)，4.27-4.39(m，3H)，6.50(s，2H)，8.02(dd，1H)，8.15-8.19(m，2H)，8.79(s，1H)。
E) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-4-cyanic acid-1H-pyrazol-1-yl) propane-2-yl)-1-methyl isophthalic acid H-imidazoles-4-methane amide
Title compound utilizes the method for embodiment 34 (d) with 1-methyl isophthalic acid H-imidazoles-4-formic acid (53.0mg; 0.420mmol) and (S)-(3-chloro-4-cyano-phenyl)-(100mg 0.350mmol) prepares as raw material 1H-pyrazoles-4-formonitrile HCN 1-(2-aminopropyl)-3-.Product is used diethyl ether and diethyl ether/ethyl alcohol recrystallization respectively and purifying.At last product is passed through purification by flash chromatography.Yield 34.1%. 1H-NMR(400MHz；DMSO-d6)：δ1.15(d，3H)，3.67(s，3H)，4.36-4.51(m，3H)，7.56(d，1H)，7.69(d，1H)，7.98(dd，1H)，8.04-8.10(m，2H)，8.15(dd，1H)，8.69(s，1H)。
Embodiment 304
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(2-hydroxy propane-2-yl)
Figure BDA0000157427790002321
azoles-4-methane amide
Title compound utilizes the method for embodiment 34 (d) with 2-(2-hydroxy propane-2-yl)
Figure BDA0000157427790002322
azoles-4-formic acid (184mg; 1.076mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(250mg 0.897mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through purification by flash chromatography.Yield 79%. 1H-NMR(400MHz；DMSO-d6)：δ1.13(d，3H)，1.52(s，6H)，4.31(dd，1H)，4.41(dd，1H)，4.44-4.52(m，1H)，5.64(s，1H)，7.02(d，1H)，7.84-7.88(m，2H)，7.97-7.98(m，1H)，8.10(d，1H)，8.48(s，1H)。
Embodiment 305
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(2-hydroxy propane-2-yl)
Figure BDA0000157427790002323
azoles-4-methane amide
Title compound utilizes the method for embodiment 34 (d) with 2-(2-hydroxy propane-2-yl) azoles-4-formic acid (197mg; 1.151mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(250mg 0.959mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.Yield 57.7%. 1H-NMR(400MHz；DMSO-d6)：δ1.12(d，3H)，1.53(s，6H)，4.31(dd，1H)，4.40(dd，1H)，4.43-4.52(m，1H)，5.66(s，1H)，6.97(d，1H)，7.84(d，1H)，7.94-8.00(m，2H)，8.08-8.10(m，1H)，8.17(d，1H)，8.48(s，1H)。
Embodiment 306
1-(5-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-1H-pyrazole-3-yl) ethyl pivalate
To containing N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-propane-2-yl)-3-(1-the hydroxyethyl)-1H-pyrazoles-5-methane amide (53mg that is dissolved in dry pyridine (2ml); 0.133mmol) solution under nitrogen, drip 2; 2-dimethyl propylene acid anhydrides (0.031ml, 0.153mmol).The mixture that forms was at room temperature stirred 2 hours, and (2.5mg 0.020mmol) and with the reaction mixture reaction spends the night to add DMAP then.Add 2 the next morning, 2-dimethyl propylene acid anhydrides (0.027ml, 0.132mmol) and with mixture under agitation again secondary response spend the night.With the mixture evaporation, with the extraction of DCM/ water and with the organic phase evaporation that merges.Product obtained 51% yield through purified. 1H-NMR(400MHz；CDCl 3)：δ1.18(d，9H)，1.21(d，3H)，1.65(d，3H)，4.25-4.32(m，1H)，4.38-4.46(m，1H)，4.55-4.65(m，1H)，5.85-5.91(m，1H)，6.61(t，1H)，6.81-6.82(m，1H)，7.51(t，1H)，7.64-7.68(m，1H)，7.73-7.77(m，1H)，7.99(d，1H)，8.17(dd，1H)。
Embodiment 307
N-((S)-1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-formamide
With (S)-5-ethanoyl-N-(1-(3-(4-cyanic acid-3,5-difluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazole-3-formamide (200mg, 0.50mmol) be dissolved in ethanol (10ml) and add Peng Qinghuana (95mg, 2.51mmol).With reaction mixture refluxed 2 hours, cooling also added saturated ammonium chloride (20ml).Mixture is used water washing with the organic grade of branch that ethyl acetate extraction also will merge for three times, dry and evaporation.Resistates is obtained (6.7mg, 3%) title compound for twice with the anti-phase purification by flash chromatography. 1H-NMR(400MHz；d6-DMSO)：δ1.13(d，3H)，1.37(d，3H)，4.24-4.40(m，2H)，4.39-4.53(m，1H)，4.72-4.84(m，1H)，6.47(s，1H)，6.98(m，1H)，7.71-7.80(m，2H)，7.79-7.88(d，1H)，8.15(d，1H)。
Embodiment 308
(S)-N-(1-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methyl different
Figure BDA0000157427790002331
azoles-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-(trifluoromethyl)-benzonitrile (120mg; 0.408mmol) and 5-methyl different
Figure BDA0000157427790002332
(62mg 0.489mmol) prepares as raw material azoles-3-formic acid.Product is used purification by flash chromatography.Yield 88mg (53%). 1H-NMR(400MHz；d6-DMSO)：δ1.16(d，3H)，2.43(s，3H)，4.32-4.34(m，2H)，4.40-4.50(m，1H)，6.43(s，1H)，7.02(d，1H)，7.84(d，1H)，8.18(d，1H)，8.23-8.25(m，1H)，8.29(s，1H)，8.71(d，1H)。
Embodiment 309
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(methoxymethyl)-1H-pyrazoles-5-methane amide
A) 5-methoxyl group-2,4-dioxo Valeric acid ethylester
(1.61g 70.0mmol) dissolves in the flask that contains dry ethanol (150ml) with the sodium of cutting into pieces under nitrogen.With syringe add oxalic acid diethyl ester (8.15ml, 60mmol) and methoxy acetone (5.52ml, 60.0mmol).The mixture that forms was at room temperature stirred 1 hour.Flask is put into ice bath and to the mixture that wherein drips sulfuric acid and frozen water.The throw out that forms is filtered and washs with DCM.With ethanol/DCM evaporation of filtrating.Resistates is dissolved in DCM, uses Na mutually with the salt solution extraction and with DCM 2SO 4Drying is filtered and evaporation.Product is used purification by flash chromatography. 1H-NMR(400MHz；DMSO-d6)：δ1.28(t，3H)，3.34(s，3H)，4.19-4.23(m，2H)，4.27(q，2H)。
B) 3-(methoxymethyl)-1H-pyrazoles-5-ethyl formate
With 5-methoxyl group-2,4-dioxo Valeric acid ethylester (2.168g, 11.52mmol) be dissolved in ethanol (100ml) and add the hydrazine dihydrochloride (4.84g, 46.1mmol).The mixture that forms was refluxed 2 hours.Add 200ml water and the pH of mixture is used NaHCO 3Neutralization.Mixture is used ethyl acetate extraction.The organic phase that merges is used brine wash, use Na 2SO 4Drying is filtered and evaporation.Product promptly can be used for next step without being further purified. 1H-NMR(400MHz；DMSO-d6)：δ1.29(t，3H)，3.26(s，3H)，4.27(q，2H)，4.42(s，2H)，6.72(s，1H)，13.62(s，1H)。
C) 3-(methoxymethyl)-1H-pyrazoles-5-formic acid
(2.44g, 13.25mmol) (8.63g 26.5mmol) joins in the flask and stirred overnight under nitrogen at room temperature with the cesium carbonate of water-soluble (40ml) will to be dissolved in 3-(methoxymethyl)-1H-pyrazoles-5-ethyl formate of methyl alcohol (40ml).Add ETHYLE ACETATE (100ml) and water (100ml) and pH is adjusted to 3 with 10% Hydrocerol A.Phase-splitting is also used ethyl acetate extraction with water.The organic phase that merges is used Na 2SO 4Drying is filtered and evaporation.Product is used purification by flash chromatography.Yield 36.5%. 1H-NMR(400MHz；DMSO-d6)：δ3.25(s，3H)，4.40(s，2H)，6.67(s，1H)，13.16(bs，2H)。
D) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(methoxymethyl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with 3-(methoxymethyl)-1H-pyrazoles-5-formic acid (0.119g; 0.759mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.165g 0.633mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.Yield 5.07%. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，3.42(s，3H)，4.27(dd，1H)，4.43(dd，1H)，4.54-4.62(m，3H)，6.62(d，1H)，6.69(s，1H)，7.49(d，1H)，7.67(d，1H)，7.75(dd，1H)，7.83(m，1H)，8.17(d，1H)。
Embodiment 310
(S)-3-ethanoyl-N-(1-(3-(4-cyanic acid-3-(trifluoromethyl) phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-(trifluoromethyl)-benzonitrile (110mg; 0.374mmol) and the 3-ethanoyl-(58mg 0.374mmol) prepares as raw material 1H-pyrazoles-5-formic acid.Product is passed through purification by flash chromatography twice.Yield 8mg (4%). 1H-NMR(400MHz；d6-DMSO)：δ1.17(d，3H)，2.48(m，3H)，4.29-4.38(m，2H)，4.41-4.50(m，1H)，7.01(d，1H)，7.29(s，1H)，7.84(d，1H)，8.15-7.19(m，1H)，8.24(s，1H)，8.44-8.50(m，2H)，14.13(m，1H)。
Embodiment 311
(R)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-methyl different
Figure BDA0000157427790002351
azoles-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with (R)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (240mg; 0.921mmol) and 5-methyl different
Figure BDA0000157427790002352
(140mg 1.105mmol) prepares as raw material azoles-3-formic acid.Product is passed through purification by flash chromatography.Yield 46mg (13%). 1H-NMR(400MHz；d6-DMSO)：δ1.15(d，3H)，4.28-4.35(m，2H)，4.40-4.50(m，1H)，6.45(d，1H)，6.93(d，1H)，7.81(d，1H)，7.91-7.93(m，1H)，7.98(d，1H)，8.07(d，1H)，8.71(d，1H)。
Embodiment 312
N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxypropyl) different
Figure BDA0000157427790002361
azoles-3-methane amide
A) 2-(penta-4-alkynes-2-base oxygen base) tetrahydrochysene-2H-pyrans
Will (+/-)-(5.58ml, 59.4mmol) with 3, (8.08ml 89mmol) is dissolved in DCM (100ml) to 4-dihydro-2H-pyrans to 4-pentyne-2-alcohol.Add 4-toluenesulphonic acids pyridinium salt (1.494g, 5.94mmol) and with the mixture that forms at room temperature with CaCl 2Pipe stirred 4 hours together.Mixture is concentrated.Add the 50ml diethyl ether, extract and use MgSO with salt solution 4Drying is filtered and evaporation.Product is without being further purified the step that promptly can be used for subsequently.LC-MS：[M+1]＝169.23。
B) 5-(2-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) propyl group) different
Figure BDA0000157427790002362
azoles-3-ethyl formate
With chloro glyoxylic acid oxime ethyl ester (1g, 6.60mmol) and 2-(penta-4-alkynes-2-base oxygen base) tetrahydrochysene-2H-pyrans (3.33g 19.80mmol) is dissolved in diethyl ether (20ml) and with the mixture vigorous stirring.The triethylamine that dropping is diluted with diethyl ether (0.920ml, 6.60mmol).Use MgSO with the extraction of reaction mixture water and with organic phase 4Drying is filtered and evaporation.Product promptly can be used for next step without being further purified.LC-MS：[M+1]＝284.32。
C) 5-(2-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) propyl group) different
Figure BDA0000157427790002363
azoles-3-formic acid
(1.87g 6.60mmol) is dissolved in THF (20ml) to different azoles-3-ethyl formate with 5-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl group).Add 1M one hydronium(ion) oxidation lithium (6.60ml) and with the mixture that forms stirred overnight at room temperature.Added 1M one hydronium(ion) oxidation lithium (3.3ml+13.20ml) in second day and with mixture stirred overnight once more.With the THF evaporation, add entry and pH is adjusted to 4 with citric acid solution.Mixture is also evaporated with ethyl acetate extraction 4 times and with the organic phase drying that merges.LC-MS：[M+1]＝256.27。
D) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) propyl group) different
Figure BDA0000157427790002371
azoles-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with 5-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl group) different
Figure BDA0000157427790002372
azoles-3-formic acid (0.392g; 1.534mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through the reverse-phase chromatography purifying.LC-MS：[M+1]＝498.97。
E) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxypropyl) different
Figure BDA0000157427790002373
azoles-3-methane amide
With N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl group) different
Figure BDA0000157427790002374
azoles-3-methane amide (0.1g; 0.201mmol), (0.5ml 1.350mmol) mixes and at room temperature stirred weekend for the EtOH solution of ethanol (2ml) and 10% hydrogenchloride.With the mixture evaporation, add ethanol and evaporation once more.Product is enough pure, need not to be further purified.Yield 51.7%. 1H-NMR(400MHz；DMSO-d6)：δ1.09(dd，3H)，1.15(d，3H)，2.82-2.86(m，2H)，3.91-3.98(m，1H)，4.29-4.34(m，2H)，4.41-4.50(m，1H)，6.48-6.50(m，1H)，6.94(d，1H)，7.82(d，1H)，7.92(dd，1H)，7.97(d，1H)，8.08-8.10(m，1H)，8.73(d，1H)。
Embodiment 313
(S)-5-((1H-imidazoles-1-yl) methyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790002375
azoles-3-methane amide
(S)-5-(brooethyl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) different
Figure BDA0000157427790002376
azoles-3-methane amide (0.328g with embodiment 197 (a); 0.731mmol) be dissolved in acetonitrile (10ml) and add the imidazoles be dissolved in acetonitrile (3ml) (0.31g, 4.55mmol).With mixture stirred overnight at room temperature.With the mixture evaporation, resistates is dissolved in ETHYLE ACETATE and water extraction.Organic phase is dry, filter and evaporation.Product is passed through with re-crystallizing in ethyl acetate purifying.Yield 13.81%. 1H-NMR(400MHz；DMSO-d6)：δ1.15(d，3H)，4.28-4.32(m，2H)，4.40-4.48(m，1H)，5.50(s，2H)，6.63(s，1H)，6.93(d，1H)，6.93-6.94(m，1H)，7.22-7.23(m，1H)，7.75-7.77(m，1H)，7.80(d，1H)，7.90(dd，1H)，7.96(d，1H)，8.07(d，1H)，8.80(d，1H)。
Embodiment 314
(S)-3-ethanoyl-4-chloro-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) 3-ethanoyl-4-chloro-1H-pyrazoles-5-methyl-formiate
To contain 3-ethanoyl-1H-pyrazoles-5-methyl-formiate (4.0g, in the flask of acetate 0.0238mol) (60ml) solution 10-12 ℃ of following Dropwise 5 % Youxiaolin (284ml, 0.190mol).Mixture is at room temperature stirred 3 evenings, and added 5% Youxiaolin at second and the 3rd day (common 177ml, 0.119mol).Water joined in the reaction mixture and with product use ethyl acetate extraction.Organic layer is used anhydrous Na 2SO 4Dry and concentrated.With crude product with twice in normal hexane recrystallization.Yield 23%.LC-MS：[M+1]＝203.5。
B) 3-ethanoyl-4-chloro-1H-pyrazoles-5-formic acid
(1.3g drips Lithium Hydroxide MonoHydrate (1.35g, water 0.032mol) (15ml) solution down at 5-10 ℃ in THF 0.0064mol) (30ml) mixture to containing 3-ethanoyl-4-chloro-1H-pyrazoles-5-methyl-formiate.Reaction mixture was at room temperature stirred 18 hours.Add cold water (15ml) and with pH with the 1N sal enixum be adjusted to～4.Product is used ethyl acetate extraction, organic layer is used anhydrous Na 2SO 4Dry and concentrated.Crude product is passed through with diethyl ether/normal hexane recrystallization purifying.Yield 56%. 1H-NMR(400MHz；DMSO-d6)：δ2.57(s，3H)，13.91(bs，1H)，14.69(s，1H)。
C) (S)-3-ethanoyl-4-chloro-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
The method that title compound utilizes embodiment 34 (d) with 3-ethanoyl-4-chloro-1H-pyrazoles-5-formic acid (0.527g, 2.79mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.56g 2.148mmol) prepares as raw material 2-benzyl chloride nitrile 4-.With product through the anti-phase purification by flash chromatography.Yield 30.8%. 1H-NMR(400MHz；DMSO-d6)：δ1.16(d，3H)，2.54(s，3H)，4.31(dd，1H)，4.37(dd，1H)，4.42-4.51(m，1H)，6.95(d，1H)，7.84(d，1H)，7.94(dd，1H)，7.98(d，1H)，8.06(d，1H)，8.27(bs，1H)，14.45(s，1H)。
Embodiment 315
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-oxopropyl) different
Figure BDA0000157427790002391
azoles-3-methane amide
A) 5-(2-hydroxypropyl) different
Figure BDA0000157427790002392
azoles-3-ethyl formate
(4g is 26.4mmol) with the 4-pentyne-(10.00ml 107mmol) is dissolved in diethyl ether (30ml) to 2-alcohol with chloro glyoxylic acid oxime ethyl ester.(3.68ml, diethyl ether 26.4mmol) (20ml) drips of solution is added in the reaction mixture with triethylamine.At room temperature stir after 1 hour reaction mixture with salt solution and water washing, use MgSO 4Drying also is evaporated to dried.Resistates is used purification by flash chromatography, obtain 2.51g (48%) title compound with the dichloromethane solution gradient elution of methyl alcohol. 1H-NMR(400MHz；d6-DMSO)：δ，1.11(d，3H)，1.31(t，3H)，2.82-2.94(m，2H)，3.93-4.03(m，1H)4.35(q，2H)，4.89(d，1H)，6.67(s，1H)。
B) 5-(2-oxopropyl) different azoles-3-ethyl formate
(1.5g 7.53mmol) is dissolved in acetone (40ml) and be cooled to 0 ℃ with 5-(2-hydroxypropyl) different
Figure BDA0000157427790002394
azoles-3-ethyl formate.(5.90ml 7.91mmol) and with reaction mixture stirred 30 minutes down at 0 ℃ to drip Jones reagent.Then reaction mixture is warming up to room temperature and stirred 18 hours.Add the mixture of methyl alcohol (30ml) and water (30ml), then volatile matter is evaporated.Resistates is extracted with DCM, use Na 2SO 4Drying also is evaporated to the dried 1.38g of obtaining (93%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ1.32(t，3H)，2.22(s，3H)，4.29-4.44(m，2H)，4.22(s，2H)，6.67(s，1H)。
C) 5-(2-oxopropyl) different azoles-3-formic acid
(0.65g 3.30mmol) is dissolved in ethanol (10ml) with 5-(2-oxopropyl) different
Figure BDA0000157427790002396
azoles-3-ethyl formate.(1.611g, water 4.94mmol) (5ml) solution join in the reaction mixture and at room temperature stirred 7 hours with cesium carbonate.Reaction mixture is concentrated, and dilute with water also is adjusted to 2 with pH with Hydrocerol A.Water is used ethyl acetate extraction, use Na 2SO 4Drying is evaporated to the dried 0.203g of obtaining (36%) title compound. 1H-NMR(400MHz；d6-DMSO)：δ，2.21(s，3H)，4.20(s，2H)，6.67(s，1H)。
D) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-oxopropyl) different
Figure BDA0000157427790002401
azoles-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.767mmol) and 5-(2-oxopropyl) different
Figure BDA0000157427790002402
(169mg 0.997mmol) prepares as raw material azoles-3-formic acid.Product is used purification by flash chromatography, obtain 101mg (32%) title compound with the DCM solution gradient wash-out of methyl alcohol. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，1.54(s，3H)，3.96(s，2H)，4.20-4.49(m，2H)，4.53-4.64(m，1H)，6.63(d，1H)，6.65-6.69(m，1H)，7.48(d，1H)，7.69(d，1H)，7.79-7.90(m，2H)，8.04(d，1H)。
Embodiment 316
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-4,5,6,7-tetrahydrochysene-2H-indazole-3-methane amide
Title compound utilizes the method for embodiment 34 (d) to use (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile, and (200mg, 0.767mmol) with 4,5,6, the 7-tetrahydrochysene-(166mg 0.997mmol) prepares as raw material 2H-indazole-3-formic acid.Product is developed with ethanol.Yield 111mg (35%). 1H-NMR(400MHz；d6-DMSO)：δ1.09(d，3H)，1.58-1.72(m，4H)，2.54-2.61(m，4H)，4.24-4.46(m，3H)，6.94(d，1H)，7.82(d，1H)，7.99(s，2H)，8.05-8.08(m，2H)，12.68(s，1H)。
Embodiment 317
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-6; 7-dihydro-4H-pyrazolo [5; 1-c] [1,4]
Figure BDA0000157427790002403
piperazine-2-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.767mmol) and 6; 7-dihydro-4H-pyrazolo [5; 1-c] [1; 4]
Figure BDA0000157427790002411
(166mg 0.997mmol) prepares as raw material piperazine-2-formic acid.Product is developed with acetonitrile.Yield 95mg (46%). 1H-NMR(400MHz；d6-DMSO)：δ1.09(d，3H)，4.09(t，2H)，4.18(t，2H)，4.26-4.39(m，2H)，4.42-4.49(m，1H)，4.79(s，2H)，6.38(s，1H)，6.95(d，1H)，7.82(d，1H)，7.97-7.99(m，2H)，8.09(s，1H)，8.26(d，1H)。
Embodiment 318
4-chloro-N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-hydroxyethyl)-1H-pyrazoles-5-methane amide
To containing Peng Qinghuana (0.044g; 1.159mmol) ethanol (10ml) mixture in slowly add embodiment 314 (S)-3-ethanoyl-4-chloro-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide (0.5g, 1.159mmol) and with temperature be warming up to 50 ℃ 10 minutes.Reaction mixture was at room temperature stirred 19 hours.Add saturated ammonium chloride (30ml) and mixture is used ethyl acetate extraction, the organic layer that merges is used Na 2SO 4Drying is filtered and evaporation.Product is used purification by flash chromatography.Yield 45.6%. 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，1.58(dd，3H)，2.88(bs，1H)，4.25-4.32(m，1H)，4.41-4.49(m，1H)，4.56-4.68(m，1H)，5.04-5.12(m，1H)，6.62(d，1H)，7.48-7.51(m，1H)，7.61-7.67(m，2H)，7.70-7.75(m，1H)，8.01-8.07(m，1H)，11.27(bs，1H)。
Embodiment 319
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-4; 5; 6,7-tetrahydro benzo [d] different
Figure BDA0000157427790002412
azoles-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (90mg; 0.345mmol) and 4; 5; 6; (75mg 0.449mmol) prepares as raw material azoles-3-formic acid 7-tetrahydro benzo [d] different
Figure BDA0000157427790002413
.Product is used purification by flash chromatography.Yield 111mg (78%). 1H-NMR(400MHz；CDCl 3)：δ1.24(d，3H)，1.69-1.83(m，4H)，2.77-2.83(m，4H)，4.25-4.43(m，2H)，4.52-4.61(m，1H)，6.63(d，1H)，7.37(d，1H)，7.49(d，1H)，7.70(d，1H)，7.86(d，1H)，7.94(d，1H)。
Embodiment 320
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-6; 7-dihydro-4H-pyrans is [3,4-d] different azoles-3-methane amide also
Title compound utilizes the method for embodiment 34 (d) with 6; 7-dihydro-4H-pyrans also [3; 4-d] different
Figure BDA0000157427790002422
azoles-3-formic acid (0.101g; 0.598mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.12g 0.460mmol) prepares as raw material 2-benzyl chloride nitrile 4-.With product through the anti-phase purification by flash chromatography.Yield 9.50%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，2.93(t，2H)，3.90(t，2H)，4.26(dd，1H)，4.42(dd，1H)，4.50-4.62(m，1H)，4.86-4.90(m，2H)，6.64(d，1H)，7.50(d，1H)，7.64(d，1H)，7.71(d，1H)，7.87(dd，1H)，7.95(d，1H)。
Embodiment 321
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(6-picoline-2-yl)-1H-imidazoles-4-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (220mg; 0.844mmol) and 1-(6-picoline-2-yl)-(223mg 1.097mmol) prepares as raw material 1H-imidazoles-4-formic acid.Product is developed with acetonitrile.Yield 153mg (40%). 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，1.45(s，3H)，2.59(s，1H)，4.28-4.45(m，2H)，4.55-4.64(m，1H)，6.62(d，1H)，7.16(d，1H)，7.19(d，1H)，7.52(d，1H)，7.67(d，1H)，7.75(t，1H)，7.80(m，1H)，7.89(d，1H)，8.12(d，1H)，8.21(d，1H)。
Embodiment 322
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyrimidine-2-methane amide
The method that title compound utilizes embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg, 0.767mmol) and imidazo [1,2-a] pyrimidine-(163mg 0.997mmol) prepares as raw material 2-formic acid.Product is developed with acetonitrile.Yield 168mg (54%). 1H-NMR(400MHz；d6-DMSO)：δ1.18(d，3H)，4.32-4.45(m，2H)，4.49-4.56(m，1H)，6.92(d，1H)，7.13-7.16(m，1H)，7.84(d，1H)，7.95(d，1H)，8.03-8.06(m，2H)，8.25(s，1H)，8.67-8.69(m，1H)，8.75(d，1H)，8.97-8.99(m，1H)。
Embodiment 323
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-flumizole [1,2-a] pyridine-2-carboxamide also
Title compound utilizes the method for embodiment 34 (d) to use (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile, and (200mg, 0.767mmol) also [1,2-a] pyridine-(180mg 0.997mmol) prepares as raw material 2-formic acid with the 3-flumizole.Product is developed with acetonitrile.Yield 217mg (67%). 1H-NMR(400MHz；d6-DMSO)：δ1.15(d，3H)，4.31-4.44(m，2H)，4.47-4.55(m，1H)，6.95(d，1H)，7.06(t，1H)，7.37(m，1H)，7.55-7.58(m，1H)，7.85(d，1H)，7.97(d，1H)，8.08(t，1H)，8.31(1H，d)，8.55(d，1H)。
Embodiment 324
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl) imidazo [1,2-a] pyrimidine-2-methane amide
Title compound utilizes the method for embodiment 34 (d) with imidazo [1; 2-a] pyrimidine-2-formic acid (0.076g; 0.466mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.1g 0.359mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through with the acetonitrile recrystallization purifying.Yield 46.0%. 1H-NMR(400MHz；CDCl 3)：δ1.32(d，3H)，4.33(dd，1H)，4.44(dd，1H)，4.57-4.67(m，1H)，6.57(dd，1H)，6.97(dd，1H)，7.50(d，1H)，7.59(dd，1H)，7.71(dd，1H)，7.80(d，1H)，8.08(s，1H)，8.47(dd，1H)，8.66(dd，1H)。
Embodiment 325
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-flumizole [1,2-a] pyridine-2-carboxamide also
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (0.1g; 0.359mmol) and 3-flumizole also [1; 2-a] (0.084g 0.466mmol) prepares as raw material pyridine-2-formic acid.Product is passed through with the acetonitrile recrystallization purifying.Yield 37.9%. 1H-NMR(400MHz；CDCl 3)：δ1.25(d，3H)，4.30(dd，1H)，4.46(dd，1H)，4.59-3.69(m，1H)，6.62(d，1H)，6.91-6.96(m，1H)，7.24-7.29(m，1H)，7.52-7.56(m，2H)，7.76-7.80(m，2H)，7.94-7.97(m，1H)，8.08(d，1H)。
Embodiment 326
(S)-and N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-4,5,6,7-tetrahydrochysene-2H-indazole-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with 4; 5,6,7-tetrahydrochysene-2H-indazole-3-formic acid (0.078g; 0.466mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.1g 0.359mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through purification by flash chromatography.Yield 65.9%. 1H-NMR(400MHz；DMSO-d6)：δ1.11(d，3H)，1.55-1.71(m，4H)，2.53-2.60(m，4H)，4.27(dd，1H)，4.35(dd，1H)，4.38-3.46(m，1H)，7.00(d，1H)，7.83-7.87(m，2H)，7.90-7.97(m，2H)，12.66(s，1H)。
Embodiment 327
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-6; 7-dihydro-5H-pyrazolo [5; 1-b] [1,3]
Figure BDA0000157427790002441
piperazine-2-methane amide
Title compound utilizes the method for embodiment 34 (d) with 6; 7-dihydro-5H-pyrazolo [5; 1-b] [1; 3]
Figure BDA0000157427790002442
piperazine-2-formic acid (0.078g; 0.466mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.1g 0.359mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through with acetonitrile recrystallization and purification by flash chromatography.Yield 53.3%. 1H-NMR(400MHz；CDCl 3)：δ1.19(d，3H)，2.26-2.34(m，2H)，4.18-4.34(m，5H)，4.41(dd，1H)，4.52-4.62(m，1H)，6.01(s，1H)，6.62(d，1H)，7.50(d，1H)，7.66(d，1H)，7.70-7.75(m，2H)。
Embodiment 328
(S)-and N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-2,4,6, the 7-tetrahydropyrans is [4,3-c] pyrazole-3-formamide also
Title compound utilizes the method for embodiment 34 (d) with 2,4, and 6; 7-tetrahydropyrans also [4; 3-c] pyrazoles-3-formic acid (0.078g, 0.466mmol) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.1g 0.359mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through with the acetonitrile recrystallization purifying.Yield 32.5%. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，2.79(t，2H)，3.89-3.94(m，2H)，4.27(dd，1H)，4.39(dd，1H)，4.48-4.58(m，1H)，4.84-4.94(m，2H)，6.61(d，1H)，7.52(d，1H)，7.65(dd，1H)，7.69(d，1H)，7.80-7.82(m，1H)。
Embodiment 329
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-4-pyridone-2-methane amide
The method that title compound utilizes embodiment 34 (d) with 5-hydroxyl-2-VPP (0.139g, 0.997mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through with the ethanol/water recrystallization purifying.Yield 22.19%. 1H-NMR(400MHz；DMSO-d6)：δ1.10(d，3H)，4.29-4.49(m，3H)，6.95(d，1H)，7.23(dd，1H)，7.83(d，1H)，7.85(d，1H)，7.98-8.00(m，2H)，8.11-8.13(m，1H)，8.17(d，1H)，8.82(d，1H)。
Embodiment 330
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(6-picoline-2-yl)-1H-imidazoles-4-methane amide
Title compound utilizes the method for embodiment 34 (d) with 1-(6-picoline-2-yl)-1H-imidazoles-4-formic acid (0.190g; 0.933mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.718mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.Product is passed through with the acetonitrile recrystallization purifying.Yield 55.3%. 1H-NMR(400MHz；DMSO-d6)：δ1.13(d，3H)，2.53(s，3H)，4.31-4.52(m，3H)，7.01(d，1H)，7.29(d，1H)，7.72(d，1H)，7.87-7.96(m，3H)，8.02-8.04(m，1H)，8.35(d，1H)，8.40(d，1H)，8.58(d，1H)。
Embodiment 331
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-7-methyl-5,6,7, the 8-imidazolidine is [1,2-a] pyrazine-2-methane amide also
A) (S)-tertiary butyl 2-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-5, the 6-glyoxalidine is [1,2-a] pyrazine-7 (8H)-manthanoate also
Title compound utilizes the method for embodiment 34 (d) with 7-(tert-butoxycarbonyl)-5; 6; 7, the 8-imidazolidine is [1,2-a] pyrazine-2-formic acid (0.044g also; 0.165mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.033g 0.127mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.LC-MS：[M+1]＝510.988。
B) (S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5,6,7, the 8-imidazolidine is [1,2-a] pyrazine-2-methane amide also, HCl
With (S)-tertiary butyl 2-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl)-5; 6-glyoxalidine also [1; 2-a] (0.029g 0.057mmol) is dissolved in the EtOH solution (0.173ml) that ethanol (2ml) also adds～10% hydrogen chloride gas to pyrazine-7 (8H)-manthanoate.The mixture that forms was at room temperature stirred 6 days, in last several days of reaction, add～the EtOH solution (0.173+0.173+2ml) of 10% hydrogen chloride gas.Evaporating solvent adds ethanol (5ml) and evaporating solvent once more.More than repeating it once.Product is passed through with the acetonitrile recrystallization purifying.LC-MS：[M+1]＝447.332。
C) (S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-7-methyl-5,6,7, the 8-imidazolidine is [1,2-a] pyrazine-2-methane amide also
With (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5,6,7, the 8-imidazolidine also [1,2-a] pyrazine-2-methane amide (23mg 0.056mmol) is dissolved in methyl alcohol (2ml).With the solution form add triethylamine (0.078ml, 0.561mmol), the aqueous solution of 37w% formaldehyde (0.067ml, 0.561mmol) and sodium cyanoborohydride (35.3mg, 0.561mmol).With the mixture that forms stirred overnight at room temperature.Reaction mixture is diluted with DCM, use NaHCO 3Solution extraction is used Na with the organic phase that merges 2SO 4Drying is filtered and evaporation.With the LC purifying of product with the MS triggering.Yield 33.6%. 1H-NMR(400MHz；CDCl 3)：δ1.26(d，3H)，2.55(s，3H)，2.90(t，2H)，3.70(d，2H)，4.08(t，2H)，4.32(dd，1H)，4.40(dd，1H)，4.54-4.65(m，1H)，6.61(d，1H)，7.48(s，1H)，7.50(d，1H)，7.67(d，1H)，7.71(d，1H)，7.81(dd，1H)，8.02(d，1H)，8.06(s，1H)。
Embodiment 332
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-6; 7-dihydro-4H-pyrans is [3,4-d] different
Figure BDA0000157427790002471
azoles-3-methane amide also
Title compound utilizes the method for embodiment 34 (d) with 6; 7-dihydro-4H-pyrans also [3; 4-d] different
Figure BDA0000157427790002472
azoles-3-formic acid (0.174g; 1.026mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.22g 0.789mmol) prepares as raw material 2-chloro-6-fluorine benzonitrile.With the LC purifying of product through the MS triggering.Yield 13.26%. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，2.93(t，2H)，3.91(t，2H)，4.27(dd，1H)，4.42(dd，1H)，4.50-4.60(m，1H)，4.89(d，2H)，6.63(d，1H)，7.37(d，1H)，7.50(d，1H)，7.59(dd，1H)，7.76-7.77(m，1H)。
Embodiment 333
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1H-imidazol-4 yl)-1; 2,4-
Figure BDA0000157427790002473
diazole-5-methane amide
A) 1H-imidazoles-4-formonitrile HCN
With the 4-formyl imidazoles (5g, 52.0mmol), (4.07g, mixture 58.5mmol) at room temperature stirred 2 hours for pyridine (30ml) and hydroxy amine hydrochloric acid salt.Then with mixture heating up to 100 ℃ and drip diacetyl oxide (9.29ml, 99mmol).At last the temperature of reaction mixture is under agitation slowly reduced to room temperature.The pH of mixture is adjusted to 7.9 with 30%NaOH.Water is used ethyl acetate extraction, the organic phase that merges is also evaporated with brine wash.Add toluene twice and evaporation.Residuum is used the toluene recrystallization, filter and crystallization is washed with DIPE. 1H-NMR(400MHz；DMSO-d6)：δ7.91(s，1H)，8.10(s，1H)，13.01(s，1H)。
B) 1-trityl-1H-imidazoles-4-formonitrile HCN
To contain trityl group chlorine (1.647g, 5.91mmol), (0.5g 5.37mmol) with in the mixture of exsiccant acetonitrile (17ml) drips triethylamine (1.295ml is 9.29mmol) and with the mixture that forms stirred overnight at room temperature 1H-imidazoles-4-formonitrile HCN.Hexane (1.6ml) and water (17ml) poured in the mixture and continue stirred 30 minutes.Throw out is filtered and vacuum-drying. 1H-NMR(400MHz；CDCl 3)：δ7.06-7.12(m，6H)，7.35-7.40(m，10H)，7.49(d，1H)。
C) (Z)-N '-hydroxyl-1-trityl-1H-imidazoles-4-carbonamidine
To contain 1-trityl-1H-imidazoles-4-formonitrile HCN (1.6g, 4.77mmol), ethanol (20ml), triethylamine (1.995ml, 14.31mmol) and hydroxy amine hydrochloric acid salt (0.663g, mixture heating up to 70 9.54mmol) ℃ also stirred 4 hours.Mixture is cooled off with ice bath, add some water (10ml), the product that deposition is separated out filters and the water thorough washing.With product 40 ℃ of following vacuum-dryings. 1H-NMR(400MHz；DMSO-d6)：δ5.43-5.50(m，2H)，7.01(d，1H)，7.04-7.13(m，6H)，7.36-7.46(m，10H)，9.10(d，1H)。
D) 3-(1-trityl-1H-imidazol-4 yl)-1; 2,4-
Figure BDA0000157427790002481
diazole-5-ethyl formate
To contain (Z)-N '-hydroxyl-1-trityl-1H-imidazoles-4-carbonamidine (1.08g, 2.93mmol) and the mixture of pyridine (20ml) be cooled to 0 ℃.(0.426ml 0.520g) and with the mixture that forms stirred 10 minutes, was warming up to room temperature then to drip the ethyl oxalyl chloride.Reaction mixture is heated to 70 ℃ and stirred 2.5 hours.Then the inclusion of flask is poured in the 50ml mixture of ice and water and with t-butyl methyl ether and extracted.Dry and the evaporation with organic phase.Product is passed through purification by flash chromatography. 1H-NMR(400MHz；DMSO-d6)：δ1.33(t，3H)，4.41(q，2H)，7.14-7.19(m，6H)，7.39-7.48(m，9H)，7.53(d，1H)，7.72(d，1H)。
E) 3-(1-trityl-1H-imidazol-4 yl)-1; 2,4-
Figure BDA0000157427790002491
diazole-5-formic acid
With 3-(1-trityl-1H-imidazol-4 yl)-1; 2; (1.1g 2.442mmol) is dissolved in ethanol (60ml) and the solution that forms is cooled to 0 ℃ to 4-
Figure BDA0000157427790002492
diazole-5-ethyl formate.With cesium carbonate (6.36g, 19.53mmol) water-soluble (25ml) and join in the solution.With reaction mixture refluxed 1 hour.With ethanol evaporation, dilute with water filters and uses water washing.With solid 40 ℃ of following vacuum-dryings.With product through with THF and re-crystallizing in ethyl acetate and purifying.LC-MS：[M+1]＝423.435。
F) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-trityl-1H-imidazol-4 yl)-1; 2,4-
Figure BDA0000157427790002493
diazole-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with 3-(1-trityl-1H-imidazol-4 yl)-1; 2; 4-
Figure BDA0000157427790002494
diazole-5-formic acid (0.211g; 0.499mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.1g 0.384mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is passed through purification by flash chromatography.LC-MS：[M+1]＝666.142。
G) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1H-imidazol-4 yl)-1; 2,4-
Figure BDA0000157427790002495
diazole-5-methane amide
To containing (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-(1-trityl-1H-imidazol-4 yl)-1; 2; 4-
Figure BDA0000157427790002496
diazole-5-methane amide (0.148g; 0.223mmol) the flask of THF (9ml) solution in add formic acid (1ml, 0.223mmol) and water (0.1ml).The mixture that forms is at room temperature stirred.In ensuing 2 days, add 7ml formic acid.Evaporating solvent adds acetonitrile and evaporation, repeats this step twice.With the LC purifying of product with the MS triggering.Yield 42.4%. 1H-NMR(400MHz；MeOD)：δ1.33(d，3H)，4.36(dd，1H)，4.45(dd，1H)，4.55-4.66(m，1H)，6.77(s，1H)，7.68-7.75(m，2H)，7.78-7.92(m，3H)，8.00(s，1H)，8.14(s，1H)。
Embodiment 334
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-oxyethyl group-4-methyl isophthalic acid H-pyrazoles-5-methane amide
A) 5-oxyethyl group-4-methyl isophthalic acid H-pyrazoles-3-ethyl formate
(9.15ml, 49.5mmol) (6.23g, ethanol 59.3mmol) (50ml) solution refluxed 1 hour with the hydrazine dihydrochloride with oxalyl propionic acid diethyl ester.Then with mixture cooling and add entry (150ml).Solution is used solid NaHCO 3Neutralization and with EtOAc extraction four times.Organic phase with salt solution and water washing, is used Na 2SO 4Drying also is evaporated to the dried 7.81g of obtaining (80%) title compound.LC-MS：[M+1]＝199.22。
B) 5-oxyethyl group-4-methyl isophthalic acid H-pyrazoles-3-formic acid
(98ml, (7.8g is in ethanol 39.4mmol) (70ml) and THF (30ml) solution 197mmol) to join 5-oxyethyl group-4-methyl isophthalic acid H-pyrazoles-3-manthanoate with the 2M sodium hydroxide solution.With reaction mixture refluxed 3 hours, evaporating solvent and water (200ml) joined in the resistates then.It is acidified to pH 1 and with EtOAc extraction three times with dense HCl.The throw out that forms in the extraction is filtered and washs with EtOAc, filtrating is evaporated to the dried 4.2g of obtaining (62%) title compound.LC-MS：[M+1]＝171.17。
C) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-3-oxyethyl group-4-methyl isophthalic acid H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with 3-oxyethyl group-4-methyl isophthalic acid H-pyrazoles-5-formic acid (0.117g; 0.690mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.15g 0.575mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is used the anti-phase purification by flash chromatography.Yield 4.21%. 1H-NMR(400MHz；DMSO-d6)：δ1.16(d，3H)，1.28(t，3H)，1.94(s，3H)，4.10-4.17(m，2H)，4.28-4.33(m，2H)，4.37-4.46(m，1H)，6.96(d，1H)，7.72(d，1H)，7.85(d，1H)，7.92(dd，1H)，7.98(d，1H)，8.07(d，1H)，12.08(s，1H)。
Embodiment 335
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxyethyl) different
Figure BDA0000157427790002511
azoles-3-methane amide
A) 5-(2-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) ethyl) different
Figure BDA0000157427790002512
azoles-3-ethyl formate
With chloro glyoxylic acid oxime ethyl ester (1g, 6.60mmol) and 2-(fourth-3-alkynyloxy base) tetrahydrochysene-2H-pyrans (3.05g 19.80mmol) is dissolved in diethyl ether (20ml).(0.668g 6.60mmol) dilutes with diethyl ether (10ml) and is added drop-wise in the aforementioned mixture with triethylamine.Use Na with the extraction of reaction mixture water and with organic layer after the adding 2SO 4Drying is filtered and evaporation.LC-MS：[M+1]＝172.17。
B) 5-(2-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) ethyl) different
Figure BDA0000157427790002513
azoles-3-formic acid
(1.77g 6.57mmol) is dissolved in THF (20ml) to different
Figure BDA0000157427790002514
azoles-3-ethyl formate with 5-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl).Add 1M one hydronium(ion) oxidation lithium (6.57ml) and the mixture that forms was at room temperature stirred 2 hours.Adding 1M one hydronium(ion) oxidation lithium (19.71ml, total amount) on the same day and with the reaction mixture stirred overnight.With the THF evaporation, add entry and pH is adjusted to 4 with citric acid solution.With mixture with ethyl acetate extraction four times.Dry and the evaporation with the organic layer that merges.LC-MS：[M+1]＝242.24。
C) N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) ethyl) different
Figure BDA0000157427790002515
azoles-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with 5-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) different
Figure BDA0000157427790002516
azoles-3-formic acid (0.222g; 0.921mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is used the anti-phase purification by flash chromatography. 1H-NMR(400MHz；DMSO-d6)：δ1.16(d，3H)，1.34-1.51(m，4H)，1.52-1.69(m，2H)，3.06(t，2H)，3.37-3.45(m，1H)，3.61-3.71(m，2H)，3.85-3.93(m，1H)，4.28-4.34(m，2H)，4.41-4.50(m，1H)，4.57-4.61(m，1H)，6.51(d，1H)，6.93(d，1H)，7.81(d，1H)，7.92(dd，1H)，7.97(dd，1H)，8.08(dd，1H)，8.74(d，1H)。
D) (S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxyethyl) different
Figure BDA0000157427790002521
azoles-3-methane amide
To containing N-((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) different
Figure BDA0000157427790002522
azoles-3-methane amide (0.04g; 0.083mmol) and the solution of ethanol (4ml) in add 10% hydrogenchloride EtOH solution (0.5ml, 1.350mmol).The mixture that forms was at room temperature stirred 2 hours.With the mixture evaporation, add 2ml diethyl ether and stirring.The product that deposition is separated out filters and uses cold heptane wash.Product is enough pure and need not to be further purified.Yield 85%. 1H-NMR(400MHz；DMSO-d6)：δ1.16(d，3H)，2.92(t，2H)，3.69(t，2H)，4.29-4.34(m，2H)，4.41-4.50(m，1H)，6.51-6.53(m，1H)，6.94(d，1H)，7.82(d，1H)，7.92(dd，1H)，7.97(dd，1H)，8.09(d，1H)，8.73(d，1H)。
Embodiment 336
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-6; 7-dihydro-5H-pyrazolo [5; 1-b] [1,3] piperazine-2-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-benzyl chloride nitrile (200mg; 0.767mmol) and 6; 7-dihydro-5H-pyrazolo [5; 1-b] [1; 3]
Figure BDA0000157427790002524
(168mg 0.997mmol) prepares as raw material piperazine-2-formic acid.Product is used purification by flash chromatography.Yield 251mg (80%). 1H-NMR(400MHz；CDCl 3)：δ1.21(d，3H)，2.27-2.32(m，2H)，4.14-4.20(m，2H)，4.26-4.43(m，4H)，4.51-4.60(m，1H)，6.01(s，1H)，6.62(d，1H)，7.49(d，1H)，7.51(d，1H)，7.66(d，1H)，7.81-7.84(m，1H)，8.03(d，1H)。
Embodiment 337
(S)-N-(1-(3-(3-chloro-4-cyanic acid-5-fluorophenyl)-1H-pyrazol-1-yl) propane-2-yl)-5-(2-hydroxy propane-2-yl) different azoles-3-methane amide
Title compound utilizes the method for embodiment 34 (d) with (S)-4-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-2-chloro-6-fluorine benzonitrile (120mg; 0.431mmol) and 5-(2-hydroxy propane-2-yl) different
Figure BDA0000157427790002526
(96mg 0.560mmol) prepares as raw material azoles-3-formic acid.Product is developed with ethanol.Yield 67mg (36%). 1H-NMR(400MHz；d6-DMSO)：δ1.17(d，3H)，1.47(s，6H)，4.31-4.33(m，2H)，4.40-4.49(m，1H)，6.49(s，1H)，7.01(d，1H)，7.84(d，1H)，7.85-7.88(m，1H)，7.99(s，1H)，8.74(d，1H)。
Embodiment 338
(S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2,4,6, the 7-tetrahydropyrans is [4,3-c] pyrazole-3-formamide also
A) (Z)-ethyl 2-hydroxyl-2-(4-oxo-2H-pyrans-3 (and 4H, 5H, 6H)-subunit) acetic ester
With two (trimethyl silyl) lithamide solution of 1M (30.0ml, 30.0mmol) and diethyl ether (40ml) under nitrogen, join in the flask and and be cooled to-72 ℃ with dry ice/acetone batch.(3g 30.0mmol) also slowly joins in the aforesaid cooling mixture with diethyl ether (10ml) dilution with tetrahydrochysene-4H-pyrans-4-ketone.The mixture that forms was stirred 1 hour down at-70 ℃.(4.07ml 30.0mmol) and with reaction mixture is warming up to room temperature and stirred overnight to add the oxalic acid diethyl ester that dilutes with diethyl ether (10ml).Formed yellow mercury oxide is filtered, with cold diethyl ether washing and 40 ℃ of following vacuum-dryings. 1H-NMR(400MHz；d6-DMSO)：δ1.16(d，3H)，1.92(t，2H)，3.68(t，2H)，3.98(q，2H)，4.19(s，2H)。
B) 2,4,6, the 7-tetrahydropyrans is [4,3-c] pyrazoles-3-ethyl formate also
With (Z)-ethyl 2-hydroxyl-2-(4-oxo-2H-pyrans-3 (and 4H, 5H, 6H)-subunit) (2.5g 12.49mmol) is dissolved in methyl alcohol (10ml) to acetic ester.(2.57g 37.5mmol) and with the mixture that forms refluxed 1 hour to add the hydrazonium salt hydrochlorate.Mixture is warming up to room temperature and evaporating solvent.Resistates is dissolved in DCM and water extracted twice.Organic layer is used Na 2SO 4Drying is filtered and evaporation.Product is used purification by flash chromatography. 1H-NMR(400MHz；d6-DMSO)：δ1.27(d，3H)，2.70(t，2H)，3.81(t，2H)，4.24(q，2H)，4.69(s，2H)，13.40(bs，1H)。
C) 2,4,6, the 7-tetrahydropyrans is [4,3-c] pyrazoles-3-formic acid also
With 2,4,6, the 7-tetrahydropyrans also [4,3-c] pyrazoles-3-ethyl formate (0.97g 4.94mmol) is dissolved in methyl alcohol (20ml) and be cooled to 0 ℃ with ice bath.(4.94ml 9.89mmol) and with mixture under agitation is cooled to room temperature to add the 2M sodium hydroxide solution.Mixture was stirred 26 hours, in this process, add 7ml 2M sodium hydroxide solution.Evaporating solvent also is adjusted to 2 with pH with 1M HCl.The throw out that forms is filtered and uses water washing.With white solid 40 ℃ of following vacuum-dryings. 1H-NMR(400MHz；d6-DMSO)：δ2.69(t，2H)，3.81(t，2H)，4.68(s，2H)，13.09(bs，1H)。
D) (S)-and N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2,4,6, the 7-tetrahydropyrans is [4,3-c] pyrazole-3-formamide also
Title compound utilizes the method for embodiment 34 (d) with 2,4, and 6; 7-tetrahydropyrans also [4; 3-c] pyrazoles-3-formic acid (0.168g, 0.997mmol) with (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is developed twice with acetonitrile.Yield 65.7%. 1H-NMR(400MHz；d6-DMSO)：δ1.11(d，3H)，2.70(t，2H)，3.72-3.80(m，2H)，4.23-4.46(m，3H)，4.56-4.68(m，2H)，6.94(d，1H)，7.82(d，1H)，7.97-8.00(m，2H)，8.07-8.09(m，1H)，8.21(d，1H)，12.98(s，1H)。
Embodiment 339
(S)-3-(1-benzyl-1H-imidazol-4 yl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
A) (Z)-4-(1-benzyl-1H-imidazol-4 yl)-1-oxyethyl group-1,4-dioxo but-2-ene-2-lithium alkoxide
(5g 24.97mmol) is dissolved in exsiccant diethyl ether (100ml) with 5-ethanoyl-1-benzyl imidazole.Mixture is cooled to-78 ℃ with dry ice/acetone batch.(27.5ml 27.5mmol) and with mixture stirred 1 hour down at-78 ℃ to drip two (trimethyl silyl) lithamide.(4.41ml 32.5mmol) and with reaction mixture is warming up to room temperature to add oxalic acid diethyl ester.With the mixture that forms stirred overnight at room temperature.The product that deposition is separated out filters, with diethyl ether washing and dry. 1H-NMR(400MHz；d6-DMSO)：δ，1.22(t，3H)，4.11(q，2H)，5.62(s，2H)，6.18(s，1H)，7.16-7.31(m，5H)，7.49(d，1H)，7.89(d，1H)。
B) 3-(1-benzyl-1H-imidazol-4 yl)-1H-pyrazoles-5-ethyl formate
To containing (Z)-4-(1-benzyl-1H-imidazol-4 yl)-1-oxyethyl group-1; 4-dioxo but-2-ene-2-lithium alkoxide (3.0g; 9.80mmol) and the suspension-s of ethanol (20ml) in add the hydrazine dihydrochloride (1.337g 12.74mmol) and with the mixture that forms under agitation refluxed 3 hours.Mixture is cooled to room temperature and mixture is evaporated.Resistates is suspended in the ethanol, stirs and filter.With throw out with cold washing with alcohol and 40 ℃ of following vacuum-dryings. 1H-NMR(400MHz；d6-DMSO)：δ1.31(t，3H)，4.33(q，2H)，5.82(s，2H)，7.18-7.37(m，6H)，8.19(s，1H)，9.42(s，1H)，14.53(bs，1H)。
C) 3-(1-benzyl-1H-imidazol-4 yl)-1H-pyrazoles-5-formic acid
(0.5g 1.687mmol) is dissolved in methyl alcohol (10ml) with 3-(1-benzyl-1H-imidazol-4 yl)-1H-pyrazoles-5-ethyl formate.Mixture is cooled to 0 ℃ and add 2M sodium hydroxide solution (1.687ml).Reaction mixture under agitation is warming up to room temperature.Stirred 2 days, and in this process, added 2M sodium hydroxide solution (3.4ml altogether).Last 1 hour 40 ℃ of stirrings down.With methyl alcohol evaporation and add entry.PH is adjusted to 1 with 1M HCl, and product precipitates from solution separates out.Mixture is filtered, with throw out with water washing and 40 ℃ of following vacuum-dryings. 1H-NMR(400MHz；d6-DMSO)：δ5.82(s，2H)，7.17-7.38(m，6H)，8.17(d，1H)，9.39(s，1H)，14.35(bs，1H)。
D) (S)-3-(1-benzyl-1H-imidazol-4 yl)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1H-pyrazoles-5-methane amide
Title compound utilizes the method for embodiment 34 (d) with 3-(1-benzyl-1H-imidazol-4 yl)-1H-pyrazoles-5-formic acid (0.268g; 0.997mmol) and (S)-(1-(2-aminopropyl)-1H-pyrazole-3-yl)-(0.2g 0.767mmol) prepares as raw material 2-benzyl chloride nitrile 4-.Product is used purification by flash chromatography.Yield 44.9%. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，4.27(dd，1H)，4.41(dd，1H)，4.53-4.63(m，1H)，5.26(s，2H)，6.61(d，1H)，6.76(s，1H)，7.00-7.05(m，2H)，7.28-7.36(m，5H)，7.49(d，1H)，7.58-7.63(m，2H)，7.78(dd，1H)，8.03(s，1H)，11.75(bs，1H)。
Embodiment 340
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(2,2-two fluoro ethyls)-2-methyl isophthalic acid H-imidazoles-4-methane amide
(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-(100mg 0.271mmol) is suspended in the acetonitrile (5ml) 2-methyl isophthalic acid H-imidazoles-4-methane amide with (S)-N-.Add 1, (0.053ml, 116mg) (124mg is 0.380mmol) and with the mixture of formation stirred overnight at room temperature with cesium carbonate for 1-two fluoro-2-iodoethane.Added 2ml THF and 50 μ l1 in second day, 1-two fluoro-2-iodoethane also continue to stir three evenings.Add 0.2ml 1,1-two fluoro-2-iodoethane and with the reaction mixture stirred overnight.Reaction mixture is evaporated.Add 3ml N, dinethylformamide also filters mixture.With the LC purifying of filtrating with the MS triggering.Yield 27.4%. 1H-NMR(400MHz；CDCl 3)：δ1.22(d，3H)，2.44(s，3H)，4.19-4.33(m，3H)，4.39(dd，1H)，4.51-4.62(m，1H)，5.82-6.13(m，1H)，6.61(d，1H)，7.49(d，1H)，7.52(s，1H)，7.64-7.71(m，2H)，7.85(dd，1H)，8.00(d，1H)。
Embodiment 341
(S)-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-1-(2-fluoro ethyl)-2-methyl isophthalic acid H-imidazoles-4-methane amide
(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl) propane-2-yl)-(100mg 0.271mmol) is suspended in the acetonitrile (5ml) 2-methyl isophthalic acid H-imidazoles-4-methane amide with (S)-N-.(124mg, 0.380mmol) (0.049ml is 0.596mmol) and with the mixture that forms stirred overnight at room temperature with 1-iodo-2-fluoroethane in mixture, to add cesium carbonate.Add entry (2ml) and mixture is evaporated.With the LC purifying of product with the MS triggering. 1H-NMR(400MHz；CDCl 3)：δ1.23(d，3H)，2.42(s，3H)，4.12-4.23(m，2H)，4.30(dd，1H)，4.39(dd，1H)，4.51-4.61(m，1H)，4.58-4.73(m，2H)，6.61(d，1H)，7.49(d，1H)，7.51(d，1H)，7.62(d，1H)，7.77(dd，1H)，7.85(dd，1H)，8.00(dd，1H)。
Embodiment 342
(S)-N-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-yl)-2-(2-hydroxy propane-2-yl) thiazole-4-carboxamide
(0.28g 0.611mmol) is dissolved in exsiccant THF to thiazole-2-manthanoate under nitrogen with (S)-ethyl 4-(1-(3-(3-chloro-4-cyanic acid-2-aminomethyl phenyl)-1H-pyrazol-1-yl) propane-2-base formamyl).Solution is cooled to-78 ℃ with acetone-the dry ice bath.Drip the Et of 3M methyl-magnesium-bromide 2O solution (0.408ml, 1.223mmol).With reaction mixture stirred overnight at room temperature.Mixture was cooled to once more in second day-78 ℃ and add the Et of 1.019ml 3M methyl-magnesium-bromide 2O solution.With mixture stirred overnight at room temperature.Add saturated ammonium chloride and the mixture water is diluted with DCM.With organic phase with salt solution and water washing.Product is passed through purification by flash chromatography.Yield 19.08%. 1H-NMR(400MHz；CDCl 3)：δ1.28(d，3H)，1.58(s，6H)，2.54(s，3H)，2.63(s，1H)，4.34(dd，1H)，4.44(dd，1H)，4.60(m，1H)，6.43(d，1H)，7.52(m，3H)，7.83(d，1H)，8.00(s，1H)。
Abb.
The THF=THF
The TFA=trifluoroacetic acid
The TEAB=tetraethylammonium bromide
The DCM=methylene dichloride
The DMF=N
EDCI=1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
The HOBt=1-hydroxybenzotriazole
The DIAD=diisopropyl azodiformate
DIPEA=N, the N-diisopropyl ethyl amine
The DMSO=DMSO 99.8MIN.
The DMAP=4-dimethyl aminopyridine
The TLC=thin-layer chromatography
The IPA=Virahol
BOC=tertiary butyl oxygen base carbonyl
The RT=room temperature
The DCC=NSC 57182

Claims (11)

1. formula (I) compound and pharmacologically acceptable salt thereof:
Figure FDA0000157427780000011
Wherein
R 1Be hydrogen, halogen, cyanic acid, nitro or optional substituted 5-or 6-unit heterocycle;
R 2Be hydrogen, halogen, cyanic acid, nitro, amino, C 1-7Alkyl, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, C 1-7Alkylthio or C 1-7Alkoxyl group;
R 3Be hydrogen, halogen or C 1-7Alkyl,
Or R 2And R 3Form optional substituted 5-or 6-unit's carbocyclic ring or heterocycle with the carbon atom that they connected;
R wherein 1, R 2And R 3In at least 2 be not hydrogen;
R 4, R 4', R 5, R 6And R 7Be hydrogen, C independently 1-7Alkyl, halo C 1-7Alkyl or hydroxyl C 1-7Alkyl;
Annular atoms E is C or N;
Dotted line is meant optional two keys;
A is a 5-12 unit heterocycle;
B is a 5-unit heterocycle, and wherein the 1-3 in the ring members is the heteroatoms that is selected from N, O and S;
R 8Be hydrogen, hydroxyl, halogen, nitro, amino, cyanic acid, oxo, C 1-7Alkyl, C 1-7Alkoxyl group, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, cyanic acid C 1-7Alkyl, amino C 1-7Alkyl, oxo C 1-7Alkyl, C 1-7Alkoxy C 1-7Alkyl, the amino C of sulfonyloxy methyl 1-7Alkyl, oxyethane C 1-7Alkyl, C 1-7Alkylamino, hydroxyl C 1-7Alkylamino, C 1-7Alkoxy C 1-7Alkylamino, C 1-7Alkylamino C 1-7Alkyl, hydroxyl C 1-7Alkylamino C 1-7Alkyl, oxyimino C 1-7Alkyl, halo C 1-7Alkyl hydroxy C 1-7Alkyl ,-C (O) R 10,-OC (O) R 17,-NH-C (O) R 18Or optional substituted 5-12 unit's carbocyclic ring or heterocycle, all groups all randomly pass through C 1-7Alkylidene group connects base and is connected on the A-ring;
R 9Be hydrogen, halogen, C 1-7Alkyl, oxo, hydroxyl C 1-7Alkyl, oxo C 1-7Alkyl or optional substituted 5 or 6 yuan of carbocyclic rings or heterocycle, all groups all randomly pass through C 1-7Alkylidene group connects base and is connected on the A-ring;
R 10Be hydrogen, hydroxyl, C 1-7Alkyl, hydroxyl C 1-7Alkyl, halo C 1-7Alkyl, C 1-7Alkoxyl group, NR 11R 12Or optional substituted 5-12 unit's carbocyclic ring or heterocycle;
R 11Be hydrogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, amino C 1-7Alkyl, C 1-7Alkylamino C 1-7Alkyl;
R 12Be hydrogen or C 1-7Alkyl;
R 13And R 14Be hydrogen, C independently 1-7Alkyl, halogen, cyanic acid or hydroxyl C 1-7Alkyl;
R 15And R 16Be hydrogen, oxo, sulfo-, C independently 1-7Alkyl or cyanic acid;
R 17Be C 1-7Alkyl, C 1-7Alkoxyl group, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl;
R 18Be C 1-7Alkyl, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl.
2. the compound of claim 1, wherein B is
Figure FDA0000157427780000021
Wherein Z is O, N, C=O or C=S;
X is C or N;
Y is C or N;
G is CH, C=O or C=S;
M is CH or O;
R 13And R 14Be hydrogen, C independently 1-7Alkyl, halogen, cyanic acid or hydroxyl C 1-7Alkyl;
Dotted line is meant optional two keys, and the point on the ring represented to be connected in asterisk.
3. claim 1 or 2 compound, wherein B is the group of formula (2 '), (3 ') or (4 ')
Figure FDA0000157427780000031
Wherein
R 13And R 14Be hydrogen, C independently 1-7Alkyl, halogen, cyanic acid or hydroxyl C 1-7Alkyl; And
The point on the ring represented to be connected in asterisk.
4. the described compound of each in the claim 1 to 3, wherein encircling A is any one in following groups or its tautomer
Figure FDA0000157427780000041
5. the described compound of each in the claim 1 to 4, wherein
Annular atoms E is C;
R 1Be halogen, C 1-7Alkyl, cyanic acid, nitro or halo C 1-7Alkyl;
R 2Be cyanic acid, halogen or nitro;
R 3Be hydrogen, halogen or C 1-7Alkyl;
A is any one in group (5 '), (6 '), (7 '), (8 '), (12 '), (20 '), (21 '), (27 ') and (28 ') or its tautomer;
B is by R 13And R 14The group of substituted formula (2 '), (3 ') or (4 '), described R 13And R 14Be hydrogen;
R 4(and R 4', if be suitable for) be hydrogen or methyl;
R 5Be hydrogen or C 1-7Alkyl;
R 6If (being suitable for) is hydrogen;
R 8Be hydrogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, halogen, oxyimino C 1-7Alkyl, 5 or 6 yuan of heterocycles or-C (O) R 10, R wherein 10Be C 1-7Alkyl, and
R 9Be hydrogen, halogen or C 1-7Alkyl.
6. formula (I ') compound and pharmacologically acceptable salt thereof are used for the purposes of the medicine of prevention or treatment androgen receptor (AR) dependent form illness in preparation
Figure FDA0000157427780000051
Wherein
R 1Be hydrogen, halogen, cyanic acid, nitro or optional substituted 5-or 6-unit heterocycle;
R 2Be hydrogen, halogen, cyanic acid, nitro, amino, C 1-7Alkyl, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, C 1-7Alkylthio or C 1-7Alkoxyl group;
R 3Be hydrogen, halogen or C 1-7Alkyl;
Or R 2And R 3Form optional substituted 5-or 6-unit's carbocyclic ring or heterocycle with the carbon atom that they connected;
R wherein 1, R 2And R 3In at least 2 be not hydrogen;
R 4, R 4', R 5, R 6And R 7Be hydrogen, C independently 1-7Alkyl, halo C 1-7Alkyl or hydroxyl C 1-7Alkyl;
Annular atoms E is C or N;
D is C or N;
Dotted line is meant optional two keys;
A is a 5-12 unit heterocycle;
B is a 5-unit heterocycle, and wherein the 1-3 in the ring members is the heteroatoms that is selected from N, O and S;
R 8Be hydrogen, hydroxyl, halogen, nitro, amino, cyanic acid, oxo, C 1-7Alkyl, C 1-7Alkoxyl group, halo C 1-7Alkyl, hydroxyl C 1-7Alkyl, cyanic acid C 1-7Alkyl, amino C 1-7Alkyl, C 1-7Alkoxy C 1-7Alkyl, the amino C of sulfonyloxy methyl 1-7Alkyl, oxyethane C 1-7Alkyl, C 1-7Alkylamino, hydroxyl C 1-7Alkylamino, C 1-7Alkoxy C 1-7Alkylamino, C 1-7Alkylamino C 1-7Alkyl, hydroxyl C 1-7Alkylamino C 1-7Alkyl, oxyimino C 1-7Alkyl, halo C 1-7Alkyl hydroxy C 1-7Alkyl ,-C (O) R 10,-OC (O) R 17,-NH-C (O) R 18Or optional substituted 5-12 unit's carbocyclic ring or heterocycle, all groups all randomly pass through C 1-7Alkylidene group connects base and is connected on the A-ring;
R 9Be hydrogen, halogen, C 1-7Alkyl, oxo or optional substituted 5 or 6 yuan of carbocyclic rings or heterocycle, all groups all randomly pass through C 1-7Alkylidene group is connected on the A-ring;
R 10Be hydrogen, hydroxyl, C 1-7Alkyl, hydroxyl C 1-7Alkyl, halo C 1-7Alkyl, C 1-7Alkoxyl group, NR 11R 12Or optional substituted 5-12 unit's carbocyclic ring or heterocycle;
R 11Be hydrogen, C 1-7Alkyl, hydroxyl C 1-7Alkyl, amino C 1-7Alkyl, C 1-7Alkylamino C 1-7Alkyl;
R 12Be hydrogen or C 1-7Alkyl;
R 13And R 14Be hydrogen, C independently 1-7Alkyl, halogen, cyanic acid, halo C 1-7Alkyl or hydroxyl C 1-7Alkyl;
R 15And R 16Be hydrogen, oxo, sulfo-, C independently 1-7Alkyl or cyanic acid;
R 17Be C 1-7Alkyl, C 1-7Alkoxyl group, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl;
R 18Be C 1-7Alkyl, amino C 1-7Alkyl or C 1-7Alkylamino C 1-7Alkyl.
7. comprise the compound of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
8. treat or prevent the method for androgen receptor dependent form situation, this method comprises the compound to the claim 1 of the individual administering therapeutic significant quantity that these needs are arranged.
9. the method for claim 8, wherein said androgen receptor dependent form situation is a prostate cancer.
10. the method for treatment or prevention androgen receptor dependent form situation, this method comprise the defined formula of claim 6 to the individual administering therapeutic significant quantity that these needs are arranged (I ') compound.
11. the method for claim 10, wherein said androgen receptor dependent form situation is a prostate cancer.
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